Abstract

Diabetic kidney disease (DKD) is among the most common complications of diabetes mellitus (DM), and remains the leading cause of end-stage renal diseases (ESRDs) in developed countries, with no definitive therapy yet available. It is imperative to decipher the exact mechanisms underlying DKD and identify novel therapeutic targets. Burgeoning evidence indicates that long non-coding RNAs (lncRNAs) are essential for diverse biological processes. However, their roles and the mechanisms of action remain to be defined in disease conditions like diabetes and DKD. The pathogenesis of DKD is twofold, so is the principle of treatments. As the underlying disease, diabetes per se is the root cause of DKD and thus a primary focus of therapy. Meanwhile, aberrant molecular signaling in kidney parenchymal cells and inflammatory cells may directly contribute to DKD. Evidence suggests that a number of lncRNAs are centrally involved in development and progression of DKD either via direct pathogenic roles or as indirect mediators of some nephropathic pathways, like TGF-β1, NF-κB, STAT3 and GSK-3β signaling. Some lncRNAs are thus likely to serve as biomarkers for early diagnosis or prognosis of DKD or as therapeutic targets for slowing progression or even inducing regression of established DKD. Here, we elaborated the latest evidence in support of lncRNAs as a key player in DKD. In an attempt to strengthen our understanding of the pathogenesis of DKD, and to envisage novel therapeutic strategies based on targeting lncRNAs, we also delineated the potential mechanisms of action as well as the efficacy of targeting lncRNA in preclinical models of DKD.

Introduction

Diabetic kidney disease (DKD) is among the most frequent complications of diabetes and has remained the leading cause of end-stage renal disease (ESRD) in developed countries for decades. It occurs in both type 1 (T1DM) and type 2 diabetes mellitus (T2DM), with a prevalence of 25–40% [1]. As the primary cause of DKD, diabetes mellitus (DM) is the most common metabolic disorder worldwide, associated with injuries of multiple organ systems in a complicated manner. The population of diabetes patients has been rising sharply in recent decades, with an estimated 387 million patients living with diabetes in 2014 and an additional 205 million new patients expected by 2035 (International Diabetes Federation 2014). In parallel, the incidence and the number of DKD patients are also significantly increased in recent years, resulting in increasingly heavy clinical, economic and social burdens. Indeed, in 2014, 44% of new cases of ESRD in the U.S.A. are caused by diabetes.

One of the salient clinical features of diabetic nephropathy (DN) is persistent urinary excretion of albumin (microalbuminuria: 30–300 mg albumin in urine per day) being an early sign of DN and macroalbuminuria (defined as urinary albumin excretion > 300 mg/day) indicative of progression of the disease. In the absence of early intervention, approximately 50% of diabetic patients with established microalbuminuria will progress to macroalbuminuria, which is associated with a ten-fold higher risk for progression to ESRD than that in patients with normalbuminuria. A progressive decline of glomerular filtration rate (GFR) and an elevated arterial blood pressure feature DN at a late stage, associated with an irreversible progression to renal failure [2]. Once entering the stage of ESRD, DKD patients will require renal replacement therapy.

Currently, clinical management of DKD mainly focuses on controlling glycemic levels, normalizing blood pressures and blocking the renin–angiotensin–aldosterone system (RAAS). Tight glycemic control may prevent the development of microvascular complications in patients with T2DM. However, it is difficult to achieve blood glucose levels in the physiological range (4–6 mmol/l when fasting and <7.8 mmol/l within 2 h of eating). In addition, tight glycemic control is no longer recommended for patients with T2DM, as it may negatively affect mortality. Furthermore, even with optimal glycemic control, a number of patients still develop DKD and progress to ESRD, suggesting the role of some glucose-independent pathogenic factors in DKD [3,4]. On the other hand, as the standard of care for DKD, inhibitors of the RAAS, including angiotensin-converting enzyme inhibitors (ACEI) and angiotensin-receptor blockers (ARB), are actually of limited efficacy in retarding the progression of renal injuries but often associated with an increased risk of hyperkaliemia and azotemia in patients with advanced DKD. Hence, there is a pressing unmet need to identify novel therapeutic targets and develop new treatments for DKD [5–7].

A growing body of evidence suggests that epigenetics is a key paradigm in the pathogenesis of DN [3,8]. As a pivotal mediator of epigenetic regulation, non-coding RNAs (ncRNAs) have attracted more and more attention. Now, along with the advances in RNA research, ncRNAs are known to play vital roles in both physiological and pathological processes [9]. According to the different length and functions, ncRNAs can be classified into several subtypes [9,10], including the long ncRNAs (lncRNAs). LncRNAs are defined by their size, namely ncRNAs exceeding 200 nucleotides, and apparently lack of protein-coding capacity [11]. It is estimated that totally there are approximately 58000 lncRNAs encoded by 91000 genes in human transcriptome, of which 3900 lncRNAs overlap with disease-associated gene variants [12]. Recent evidence indicates that lncRNAs are essential for a number of biological processes, such as chromatin modification, transcriptional regulation, post-transcriptional regulation, cellular proliferation, differentiation and apoptosis. Although more and more lncRNAs are being characterized, their roles and the underlying mechanisms of action remain unclear in disease conditions like DKD. Here, we delineated the latest evidence regarding the roles of lncRNAs in the pathogenesis of diabetes and DKD. These new findings may pave the way for lncRNAs to serve as novel biomarkers for early diagnosis or prognosis of DKD or as therapeutic targets for treating DKD [13,14].

General characteristics of lncRNAs

Similar to other ribonucleic acids, lncRNAs could localize to the nucleus, cytoplasm or both (Figure 1). Nuclear lncRNAs may mediate epigenetic regulations via a variety of modes, including serving as transcriptional co-activators, affecting DNA methylation or histone modifications, and titrating transcription factors and other proteins away from chromatin (Figures 1 and 2). In contrast, cytoplasmic lncRNAs may act as a molecular sponge and bind with microRNAs (Figures 1 and 2), indirectly enhancing protein expression [9,10]. According to their subcellular localization patterns, their relationship with adjacent or homology protein-coding genes, their interaction with other macromolecules and their biological functions, lncRNA can be categorized into different types. Currently, there are six categories of lncRNA based on their relationship with adjacent or homology protein-coding genes (Figure 1), known as: (A) divergent (pancRNA: they originate from the opposite strand of the same promoter region of protein coding gene as the adjacent) and convergent (they encoded on opposite strands and face each other); (B) intronic (they are transcribed from an intron of another gene); (C) intergenic (lincRNA: they are located far from other genes, usually >10 kb); (D) overlapping sense (they overlapped with other genes on the same strand) and overlapping antisense (they overlapped with other genes on the opposite strand); E) enhancer RNA (they are expressed as uni- or bidirectional transcripts; gene enhancers could participate in many programs of gene activation by targeting some specific promoters); and F) miRNA host gene. LncRNAs are able to bind with proteins, RNAs, and DNAs through RNA–protein, RNA–RNA and RNA–DNA interactions to form functional complexes and play important biological roles in multiple cellular processes [15–17]. Based on their biological functions (Figure 2), lncRNAs are further categorized into four subtypes, i.e. guide-, decoy-, signals- and scaffold-lncRNAs. Guide-lncRNAs directly bind to specific protein targets as guides, such as chromatin modifiers—including imprinting and X-chromosome inactivation, recruitment of chromatin-modifying enzymes to target genes in cis- or trans chromatin remodeling, and epigenetic regulation of target genes. The decoy function involves binding of microRNAs to lncRNAs (miR sponges), titration of transcription factors away from chromatin, or recruitment of protein factors into nuclear subdomains, serving as competing endogenous RNA (ceRNA). The signal function of may regulate the expression of other genes, wherein lncRNAs act as a signaling molecule that may promote or repress gene transcription, or control gene splicing. The scaffold function of lncRNAs involves the molecules acting as a central platform to assemble relevant molecular components and regulate the intermolecular interactions and signaling events, often accompanied by allosteric modification of protein activity [15,18–23]. Unlike other ribonucleic acids, lncRNAs have a relatively low expression abundance and poor sequence conservation among different species. However, lncRNAs participate in many important biological processes and exert crucial functions. In addition, lncRNA expression is highly tissue- and cell-specific. As such, lncRNAs have the potential to serve as candidate biomarkers for various diseases [21,24–27].

Classifications of lncRNAs based on their subcellular localization patterns, their relationship with adjacent or homology protein-coding genes, their interaction with other macromolecules and their biological functions

Figure 1
Classifications of lncRNAs based on their subcellular localization patterns, their relationship with adjacent or homology protein-coding genes, their interaction with other macromolecules and their biological functions

Based on the subcellular localization patterns, there are three categories of lncRNAs: nuclear, cytoplasmic or both. There are six categories of lncRNAs based on their relationship with adjacent or homology protein-coding genes: (A) Divergent (pancRNA: They originate from the opposite strand of the same promoter region of protein-coding gene as the adjacent) and convergent (they are encoded by the opposite strands and face each other). (B) Intronic (they are transcribed from an intron of another gene). (C) Intergenic (lincRNA: they are located far from other genes, usually >10 kb). (D) Overlapping sense (they overlap with other genes on the same strand) and overlapping antisense (they overlap with other genes on the opposite strand. Antisense transcripts are transcribed from the opposite direction of the protein-coding gene and contain complementary sequences to the correspondingly mature mRNA. They can be located in both the cytoplasm and nucleus, and play multiple cellular roles, such as transcriptional regulation, mRNA stabilization, splicing and epigenetic control). (E) Enhancer RNA (they are expressed as uni- or bidirectional transcripts; gene enhancers could participate in many programs of gene activation by targeting some specific promoters). (F) miRNA host gene. There are three categories of lncRNAs based on their interaction with other macromolecules: RNA–RNA, RNA–DNA, RNA–protein. There are four categories of lncRNAs based on their biological functions: guide, decoy, signal, scaffold.

Figure 1
Classifications of lncRNAs based on their subcellular localization patterns, their relationship with adjacent or homology protein-coding genes, their interaction with other macromolecules and their biological functions

Based on the subcellular localization patterns, there are three categories of lncRNAs: nuclear, cytoplasmic or both. There are six categories of lncRNAs based on their relationship with adjacent or homology protein-coding genes: (A) Divergent (pancRNA: They originate from the opposite strand of the same promoter region of protein-coding gene as the adjacent) and convergent (they are encoded by the opposite strands and face each other). (B) Intronic (they are transcribed from an intron of another gene). (C) Intergenic (lincRNA: they are located far from other genes, usually >10 kb). (D) Overlapping sense (they overlap with other genes on the same strand) and overlapping antisense (they overlap with other genes on the opposite strand. Antisense transcripts are transcribed from the opposite direction of the protein-coding gene and contain complementary sequences to the correspondingly mature mRNA. They can be located in both the cytoplasm and nucleus, and play multiple cellular roles, such as transcriptional regulation, mRNA stabilization, splicing and epigenetic control). (E) Enhancer RNA (they are expressed as uni- or bidirectional transcripts; gene enhancers could participate in many programs of gene activation by targeting some specific promoters). (F) miRNA host gene. There are three categories of lncRNAs based on their interaction with other macromolecules: RNA–RNA, RNA–DNA, RNA–protein. There are four categories of lncRNAs based on their biological functions: guide, decoy, signal, scaffold.

Mechanistic scheme of biological functions of lncRNAs

Figure 2
Mechanistic scheme of biological functions of lncRNAs

LncRNAs regulate target gene expression via (1) interacting with transcriptional activators and promoting target gene transcription; (2) mediating transcriptional repression by directly affecting transcriptional repressor signaling or by acting as decoy to titrate transcriptional activators away from chromatin; (3) recruiting chromatin-modifying complexes as lineage–specific gene enhancers. (4) Acting as scaffolding proteins and recruiting chromatin-remodeling complexes; (5) directing RNA splicing either by interacting with splicing factors or by binding to splicing junctions of pre–mRNA; (6) acting as molecular sponges and competitively binding to miRNA. Abbreviations: EED, embryonic ectoderm development; GTF, general transcription factor; Pol II, RNA polymerase II; PRC2, polycomb repressive complex 2; SUZ12, PRC2 subunit; TF, transcription factor.

Figure 2
Mechanistic scheme of biological functions of lncRNAs

LncRNAs regulate target gene expression via (1) interacting with transcriptional activators and promoting target gene transcription; (2) mediating transcriptional repression by directly affecting transcriptional repressor signaling or by acting as decoy to titrate transcriptional activators away from chromatin; (3) recruiting chromatin-modifying complexes as lineage–specific gene enhancers. (4) Acting as scaffolding proteins and recruiting chromatin-remodeling complexes; (5) directing RNA splicing either by interacting with splicing factors or by binding to splicing junctions of pre–mRNA; (6) acting as molecular sponges and competitively binding to miRNA. Abbreviations: EED, embryonic ectoderm development; GTF, general transcription factor; Pol II, RNA polymerase II; PRC2, polycomb repressive complex 2; SUZ12, PRC2 subunit; TF, transcription factor.

Involvement of lncRNAs in diabetes

As the underlying disease, diabetes per se is the root cause of DKD and thus a primary focus of therapy. Diabetes is a chronic metabolic disorder resulting from insulin deficiency or resistance and it is always associated with multi-system complications, such as nephropathy, retinopathy, neuropathy and cardiovascular diseases [28,29]. Based on the status of insulin inadequacy, diabetes is categorized into two common forms: T1DM and T2DM [30].

T1DM accounts for approximately 5–10% of all diabetes and is primarily caused by chronic autoimmune injury to pancreatic β cells, resulting in an absolute deficit of insulin. The key pathological features are insulitis, β-cell loss, and hyperexpression of human leukocyte antigens class I. Genetic factors have an important role in its appearance and progression [31]. In contrast, T2DM, usually manifesting as hyperinsulinemia, is a metabolic disorder characterized by chronic hyperglycemia secondary to insulin resistance [32]. T2DM and its complications are classical diseases as a result of interactions between multiple genetic and environmental factors. Agents currently used for treating diabetes often focus on promoting insulin secretion and (or) increasing insulin sensitivity because absolute or relative insulin deficiency is the key etiology of diabetes. However, these medications are not without limitations [33]. Most importantly, the current therapies seem to have limited benefit on diabetic complications like DKD. Therefore, there is a pressing need to understand the pathogenic mechanism of DKD and explore novel and effective therapeutic targets.

The role of lncRNAs in metabolic homeostasis and diseases, especially in diabetes, is now much better deciphered than before. Recent studies have shown that lncRNAs play an important role in regulating β-cell function, insulin secretion, and the development of insulin resistance [16,45,46]. Totally, approximately 1128 lncRNAs have been identified in human islet cells, and a number of them are highly islet-specific relative to non-islet tissues. These islet-specific lncRNAs are often located close to islet-specific chromatin domains and coding genes [34–36]. This is consistent with another study, which confirmed 148 β-cell-specific lncRNAs, suggesting that they may have important and unique roles in regulating pancreatic and β-cell functions [37]. However, the precise mechanisms need to be further delineated.

LncRNAs and T1DM

During the initial phases of T1DM, cytokines and other inflammatory mediators, released by infiltrating immune cells, could perturb islet gene expression and progressively cause islet injury, ultimately leading to β-cell apoptosis and loss [38–41]. Nevertheless, the changes of lncRNA expression in T1DM and the underlying mechanisms have not been fully understood.

In vitro, in a pancreatic β-cell line (MIN6) exposed to a combined treatment of IL-1β, TNF-α and IFN-γ, the expression profiles of lncRNAs and mRNAs were assessed by microarray technology [42]. Totally, 723 differentially expressed lncRNAs and 2180 differentially expressed mRNAs were identified in the cytokine-stimulated group compared with the control group. Among these lncRNAs, 444 were up-regulated and 279 were down-regulated [43]. NONMMUT036704 is the most up-regulated lncRNA, and exhibits sense overlap with lipocalin 2 (Lnc2), which plays an important role in a number of diseases via inducing proinflammatory mediators [42]. NONMMUT034373 is another highly up-regulated lncRNA and has sense overlapping with CD274 antigen (Cd274), also known as programmed death-1 ligand-1 (PD-L1), which was significantly decreased in autoimmune diabetes [42,44]. In addition, chromatin immunoprecipitation (ChIP) experiments using freshly isolated human islets have demonstrated that insulin-like growth factor 2 (Igf2) antisense RNA (IGF2-AS) was associated with the susceptibility to T1DM [26]. In vitro, in β cells stimulated by high concentration of glucose, the expression of IGF2-AS was up-regulated, concomitant with a potentially promoted β-cell proliferation [45]. Another lncRNA, Plasmacytoma variant translocation 1 (PVT1), is a 1.9-kb long lncRNA and encodes a number of alternative transcripts. It is able to increase proliferation and inhibit apoptosis in multiple cell types [46,47]. The genotyping data of PVT1 variants from the Genetics of Kidneys in Diabetes (GoKinD) study showed a strong association between PVT1 variants and ESRD that is attributable to T1DM. Furthermore, PVT1 expression in diverse renal cell types has been validated [46,47].

Maternally expressed mouse gene 3 (MEG3) is a novel lncRNA regulator of insulin synthesis, secretion and sensitivity [27,48]. In humans, genome-wide association studies (GWASs) revealed a single nucleotide polymorphism (SNP, rs941576: A>G), located in an intron of MEG3, has an association with T1DM [49]. This is in agreement with the finding that MEG3 expression is reduced in β cells in murine models of T1DM and T2DM. Consistently, in vitro in pancreatic β-cell line MIN6 exposed to high ambient glucose, MEG3 expression was mitigated [12,50,51]. Moreover, knockdown of MEG3 by using small interfering RNA in MIN6 cell line cultured in normal ambient glucose potentiates β-cell apoptosis, suggesting an essential role for MEG3 in maintaining β-cell viability. In addition, knockdown of MEG3 by siRNA in wild-type Babl/c mice diminished insulin synthesis and secretion, leading to impaired glucose tolerance (IGT) [50]. In contrast, overexpression of MEG3 by full length-expressed lentivirus transfection significantly suppressed the proliferation and angiogenesis of vascular endothelial cells, underscoring a possible role of MEG3 in diabetic vascular disease. MEG3 may exert this effect by acting as a microRNA sponge and negatively regulating mir-9 [52]. Although these lncRNAs are vitally implicated in β-cell regulation and in T1DM, the underlying molecular mechanisms are obscure.

LncRNAs and T2DM

T2DM, accounting for more than 90% of the diabetic population, is a multifactorial disease that involves genetic, environmental, socio-economic and behavioral factors [53,54]. GWAS in T2DM patients found that the SNP variants of lncRNA genes are associated with T2DM. This provided the potential evidence that dysregulation of lncRNAs may play a pathophysiological role in T2DM [55].

One of the important roles of lncRNA is acting as microRNA sponges and serve as ceRNA. Recently, a T2DM-related ceRNA network was successfully constructed by including a total of 632 human T2DM-related genes derived from the Text-mined Hypertension, Obesity and Diabetes candidate gene database (T-HOD) and the Online Mendelian Inheritance in Man (OMIM) Morbid Map. A total of 98 genes, 86 microRNAs and 167 lncRNAs were involved in this T2DM-related ceRNA network [56]. After gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, mTOR subnetwork was identified to be an important one, in accordance with the central role of mTOR in energy and metabolic homeostasis. The mTOR subnetwork consists of mTOR gene, 3 microRNAs and 15 lncRNAs. Eventually, two ceRNA pairs, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1)-mir-144-mTOR and NEAT1-mir-181b-Mtor, were successfully validated, but the mechanisms and functions need to be defined [56].

Apart from these two lncRNAs, many other lncRNAs are also associated with T2DM possibly via different mechanisms, such as affecting insulin secretion, insulin resistance, or both. Taurine-upregulated gene 1 (TUG1), an islet-enriched lncRNA, was reported to be involved in the regulation of insulin secretion. Yin et al. [57] found that silencing of TUG1 via specific small interfering RNA increased islet cell apoptosis and reduced insulin secretion both in vitro and in vivo conditions. Mechanistically, knockdown of TUG1 in cultured non-β cells reduced the mRNA levels of transcription factors related to insulin synthesis/secretion, such as pancreatic and duodenal homeobox 1 (Pdx1), neurogenic differentiation 1 (NeuroD1), v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), and glucose transporter 2 (Glut2) [58,59]. In the T2DM-related ceRNA network, TUG1 was also predicted to modulate the EP300 gene expression by binding with mir-31 [56].

The lncRNA ANRIL (antisense noncoding RNA in the INK4 locus), also known as cdkn2b, was consistently discovered by three GWASs to associate with the risk of T2DM. ANRIL might contribute to maintaining glucose homeostasis and promoting β-cell division by repressing the expression of cyclin-dependent kinase inhibitor 2a (Cdkn2a) in mice. Cdkn2a was up-regulated with the ageing of the islets in mice and thus limited the regenerative capacity of β cells [60,61].

Another lncRNA, Kcnq1ot1, is expressed in the pancreas and is transcribed from an imprinted locus containing the potassium voltage-gated channel subfamily q member 1 (Kcnq1) gene, which encodes a voltage-gated potassium channel [62]. A variant of Kcnq1ot1 associated with T2DM was recently identified by GWAS [63]. Further analyses of SNP in human fetal samples revealed an increased methylation at this locus [64]; however, there was no concomitant change in gene expression of Kcnq1 or Kcnq1ot1 [65]. In contrast, a separate study on sequence-based transcriptome and chromatin maps of human islets and β cells found elevated Kcnq1ot1 transcript levels in human T2DM islets [66]. Thus, the actual relationship between Kcnq1ot1 and T2DM still needs further validation.

The lncRNA H19, localized to both cytoplasm and nucleus, is highly expressed in both human and mouse skeletal muscle. It was found to be reduced by five-fold in the muscle of both diabetic human patients and insulin-resistant mice [67,68]. A relationship between H19 and Igf2 was determined by using transgenic mice with the silencing of the cis-H19 promoter [69]. Through cross-linking and genome-wide transcriptome analysis, H19 was also found to regulate glucose homeostasis by acting as a molecular sponge for mir-let-7 in vivo. Mechanistically, H19 binds to mir-let-7 and prevents mir-let-7 from inhibiting the expression of target genes including the genes encoding insulin receptor and lipoprotein lipase in muscle cells [67]. These data illustrated the potential roles of H19 in insulin resistance.

The lncRNA SRA (Steroid Receptor RNA Activator) enhances adipogenesis and increases both glucose uptake and phosphorylation of AKT and FOXO1 in response to insulin [70]. To decipher the mechanism, mouse adipocytes overexpressing the human SRA isoform 2 were employed. It was found that SRA overexpression promoted full adipogenesis partially by stimulating insulin/insulin-like growth factor-1 (IGF-1) signaling and inhibiting phosphorylation of p38 mitogen activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK). Conversely, knockdown of endogenous SRA by shRNA increased phosphorylation of JNK and reduced insulin receptor mRNA and protein levels in mature adipocytes [70,71].

The lncRNA MEG3, which is implicated in T1DM, may also play an important role in T2DM. High-throughput sequencing of small RNAs in islets isolated from non-diabetic or T2DM organ donors demonstrated that the δ-like non-canonical notch ligand 1 (dlk1)-MEG3 miRNA cluster was highly and specifically expressed in human β cells, but strongly repressed in islets from T2DM donors [72]. By performing ChIP-seq and lentivirus-based RNA interference in mouse embryonic stem cells, MEG3 was found to silence the imprinted paternal dlk1 locus by recruitment of polycomb repressive complex 2 (PRC2) [73]. On the other hand, up-regulation of MEG3 could enhance hepatic insulin resistance via increasing Foxo1 expression in high-fat diet mice, ob/ob mice and mice primary hepatocytes [74]. This may be one of the potential mechanisms for MEG3’s role in insulin resistant.

LncRNA HOTTIP (HOXA distal transcript) is transcribed from the 5′-end of the HOXA gene. Evidence suggests that HOTTIP participates in chromatin spatial conformation, histone modification and composition of nuclear complexes. It modulates gene expressions and is closely related to the pathological processes of many diseases, including diabetes. HOTTIP was down-regulated in islet tissues in diabetic db/db mice. Inhibition of HOTTIP by shRNA attenuated insulin secretion and reduced expressions of Pdx1 and MafA. Down-regulation of HOTTIP also inhibited cell proliferation and reduced expressions of CyclinDl, CyclinD2, CyclinE1 and CyclinE2. Moreover, islet β cells were arrested in the G0/G1 phase after HOTTIP knockdown. These data suggest the important biological function of HOTTIP in regulating insulin secretion and cell cycle in islet β cells [75].

Another genome-wide analysis was performed on 115352 SNPs in pools of 105 unrelated case subjects with ESRD and 102 unrelated control subjects who have had T2DM for at least 10 years without macroalbuminuria. Subsequently, three SNPs showing substantial differences in allelic frequency between case and control pools were identified by a sliding window statistic of ranked SNPs. They were located in PVT1, which has been reported to associate with ESRD in T1DM patients. Together, these data suggest that PVT1 may also contribute to ESRD susceptibility in T2DM [76].

Many other lncRNAs also display a close relationship with T2DM. However, their roles in T2DM as well as the underlying mechanisms are still unknown. The expressions of the lncRNA LY86-AS1 and HCG27_201 were profiled in peripheral blood mononuclear cells collected from 100 T2DM and 100 non-diabetic subjects and found to be down-regulated in the T2DM and negatively correlate with fasting blood glucose levels. On the receiver operating characteristic (ROC) analysis, LY86-AS1 exhibited the potential role to serve as a diagnostic marker for T2DM [77]. Likewise, growth arrest-specific transcript 5 (GAS5), which was decreased in T2DM patients’ serum, is another lncRNA associated with T2DM, and may be used as a biological marker for early diagnosis and prediction [25,27]. Natural antisense to PINK1 (naPINK1) is expressed in muscle and adipose tissues and has been associated with obesity and T2DM (Table 1) [78,79].

Table 1
LncRNAs involved in DM
Disease LncRNAs 
T1DM NONMMUT036704; NONMMUT034373; PVT1; MEG3; IGF2-AS 
T2DM MALAT1; NEAT1; TUG1; ANRIL; Kcnq1ot1; H19; SRA; MEG3; GAS5; naPINK1; LY 86-AS1; HCG27-201; HOTTIP; PVT-1 
Disease LncRNAs 
T1DM NONMMUT036704; NONMMUT034373; PVT1; MEG3; IGF2-AS 
T2DM MALAT1; NEAT1; TUG1; ANRIL; Kcnq1ot1; H19; SRA; MEG3; GAS5; naPINK1; LY 86-AS1; HCG27-201; HOTTIP; PVT-1 

In summary, more and more evidence suggests a potential role of lncRNAs in the pathogenesis of diabetes. LncRNAs might be a new regulator of diabetes-related signaling pathways. Therapeutic targeting of lncRNAs is likely able to enhance insulin secretion and sensitivity [26].

The role of lncRNAs in diabetes-related kidney injuries

The pathogenesis of DKD is highly complicated. Numerous histologic changes are involved in the development of DKD, including thickening of glomerular basement membrane, mesangiolysis and mesangial expansion, extracellular matrix (ECM) accumulation, arteriosclerosis, podocytes injury and tubulopathy. A multitude of additional pathogenic processes are also implicated, including inflammation, advanced glycation end product (AGE) accumulation, oxidative stress, ER stress, activation of the polyol pathway and so on. More recently, increasing data indicated that ncRNAs, especially lncRNAs, play key roles in the progress of DKD (Table 2) [80,81].

Table 2
LncRNAs involved in DKD
LncRNAs Target cells References Mechanisms 
MALAT1 Podocytes Hu et al. [83MALAT1 is dysregulated in DN and involved in high glucose-induced podocyte injury via its interplay with β-catenin 
 Glomerular endothelial cells Liu et al. [95Knockdown of MALAT1 reduces endothelial cell migration, prevents the hyper-proliferation of endothelial cells through p38 MAPK signaling, and attenuates the generation of reactive oxygen species in endothelial cells exposed to high glucose 
 Renal tubular cells Liu et al. [95Regulates renal tubular epithelial apoptosis and new tubule formation 
  Lelli et al. [125 
  Li et al. [126 
TUG1 Podocytes Li and Susztak [84Responsible for metabolic alterations. Participate in the regulation of mitochondrial function in podocytes 
  Long et al. [85 
 Mesangial cells Duan et al. [105Inhibits the high glucose-elicited expression of fibrogenic molecules 
MAIT Glomerular endothelial cells Gong and Su [91lncRNA-MIAT interacts with mir-150-5p through a ceRNA mechanism and modulates endothelial expression of VEGF 
  Yan et al. [92 
 Renal tubular cells Zhou et al. [93Enhances the Nrf2 stability and regulate proximal tubular cell viability 
GM5524 Podocytes Feng et al. [86Induces podocyte apoptosis and cell autophagy 
GM15645 Podocytes Feng et al. [86Suppresses podocyte apoptosis and cell autophagy 
LINC01619 Podocytes Bai et al. [87Triggers oxidative stress and podocyte injuries 
CYP4B1-PS1-001 Mesangial cells Wang et al. [100Inhibits the proliferation and fibrosis of mesangial cells 
ENSMUST00000147869 Mesangial cells Tang et al. [101Protects mesangial cells from proliferation and fibrosis 
PVT1 Mesangial cells Millis et al. [46Associated with ESRD in patients with T2DM; increases the expression of a number of fibrogenic molecules in mesangial cells, including TGF-β1, PAI-1 and fibronectin 
  Colombo et al. [103 
  Alvarez et al. [104 
ASncmtRNA-2 Mesangial cells Gao et al. [109Contributes to glomerular fibrosis in DKD via promoting the expression of profibrotic factors 
Rp23 Mesangial cells Kato et al. [106Induces mesangial cell proliferation and hypertrophy 
Cj241444 Mesangial cells Kato et al. [107Induces mesangial cell proliferation and hypertrophy 
MGC Mesangial cells Kato et al. [108Up-regulated by TGF-β1 or high glucose in mesangial cells 
Erbb4-ir Mesangial cells Zhou et al. [110Suppresses TGF-β/smad3-mediated renal fibrosis; suppresses mir-29b expression 
  Long and Danesh [111 
  Sun et al. [112 
NONHSAG053901 Mesangial cells Peng et al. [113Promote proinflammatory cytokines via stimulating Egr-1/TGF-β-mediated renal inflammation 
Gm6135 Mesangial cells Ji et al. [114Induces cell proliferation and apoptosis 
Linc00968 Mesangial cells Li et al. [115Induces cell proliferation, cycle progression and the ECM proteins expression 
Gm4419 Mesangial cells Dabek et al. [118Induces the expressions of proinflammatory cytokines and biomarkers of renal fibrosis 
Dars-as1 Renal tubular cells Mimura et al. [124Blunts apoptotic cell death triggered by hypoxia 
E330013P06/MIR143HG Macrophages Reddy et al. [130Triggers the expression of a number of proinflammatory and proatherogenic genes activated by high glucose treatment 
LncRNA uc.48+ Macrophages Wu et al. [132Evokes P2X7R–mediated immune and inflammatory responses through several means, including cytokine secretion, reactive oxygen species formation, and activation of the ERK signaling pathway. 
LncRNA Dnm3os Macrophages Das et al. [133Alter global histone modifications, up-regulated inflammation, immune response genes and phagocytosis via binding with nucleolin and ILF-2 
LncRNA lethe Macrophages Miranda-Diaz et al. [135Eliminates the increased ROS production induced by high glucose conditions, while also attenuating the up-regulation of Nox2 expression 
SENCR Vascular smooth muscle cells Zou et al. [137Reverses the inhibitory effect of high glucose on the proliferation and migration of mouse vascular smooth muscle cells 
GAS5 Vascular smooth muscle cells Carter et al. [138A risk factor for diabetes 
  Wang et al. [139A potent regulator of endothelial and vascular smooth muscle cells function and contributes to hypertension-related remodeling of arteries, like renal arteries 
LncRNAs Target cells References Mechanisms 
MALAT1 Podocytes Hu et al. [83MALAT1 is dysregulated in DN and involved in high glucose-induced podocyte injury via its interplay with β-catenin 
 Glomerular endothelial cells Liu et al. [95Knockdown of MALAT1 reduces endothelial cell migration, prevents the hyper-proliferation of endothelial cells through p38 MAPK signaling, and attenuates the generation of reactive oxygen species in endothelial cells exposed to high glucose 
 Renal tubular cells Liu et al. [95Regulates renal tubular epithelial apoptosis and new tubule formation 
  Lelli et al. [125 
  Li et al. [126 
TUG1 Podocytes Li and Susztak [84Responsible for metabolic alterations. Participate in the regulation of mitochondrial function in podocytes 
  Long et al. [85 
 Mesangial cells Duan et al. [105Inhibits the high glucose-elicited expression of fibrogenic molecules 
MAIT Glomerular endothelial cells Gong and Su [91lncRNA-MIAT interacts with mir-150-5p through a ceRNA mechanism and modulates endothelial expression of VEGF 
  Yan et al. [92 
 Renal tubular cells Zhou et al. [93Enhances the Nrf2 stability and regulate proximal tubular cell viability 
GM5524 Podocytes Feng et al. [86Induces podocyte apoptosis and cell autophagy 
GM15645 Podocytes Feng et al. [86Suppresses podocyte apoptosis and cell autophagy 
LINC01619 Podocytes Bai et al. [87Triggers oxidative stress and podocyte injuries 
CYP4B1-PS1-001 Mesangial cells Wang et al. [100Inhibits the proliferation and fibrosis of mesangial cells 
ENSMUST00000147869 Mesangial cells Tang et al. [101Protects mesangial cells from proliferation and fibrosis 
PVT1 Mesangial cells Millis et al. [46Associated with ESRD in patients with T2DM; increases the expression of a number of fibrogenic molecules in mesangial cells, including TGF-β1, PAI-1 and fibronectin 
  Colombo et al. [103 
  Alvarez et al. [104 
ASncmtRNA-2 Mesangial cells Gao et al. [109Contributes to glomerular fibrosis in DKD via promoting the expression of profibrotic factors 
Rp23 Mesangial cells Kato et al. [106Induces mesangial cell proliferation and hypertrophy 
Cj241444 Mesangial cells Kato et al. [107Induces mesangial cell proliferation and hypertrophy 
MGC Mesangial cells Kato et al. [108Up-regulated by TGF-β1 or high glucose in mesangial cells 
Erbb4-ir Mesangial cells Zhou et al. [110Suppresses TGF-β/smad3-mediated renal fibrosis; suppresses mir-29b expression 
  Long and Danesh [111 
  Sun et al. [112 
NONHSAG053901 Mesangial cells Peng et al. [113Promote proinflammatory cytokines via stimulating Egr-1/TGF-β-mediated renal inflammation 
Gm6135 Mesangial cells Ji et al. [114Induces cell proliferation and apoptosis 
Linc00968 Mesangial cells Li et al. [115Induces cell proliferation, cycle progression and the ECM proteins expression 
Gm4419 Mesangial cells Dabek et al. [118Induces the expressions of proinflammatory cytokines and biomarkers of renal fibrosis 
Dars-as1 Renal tubular cells Mimura et al. [124Blunts apoptotic cell death triggered by hypoxia 
E330013P06/MIR143HG Macrophages Reddy et al. [130Triggers the expression of a number of proinflammatory and proatherogenic genes activated by high glucose treatment 
LncRNA uc.48+ Macrophages Wu et al. [132Evokes P2X7R–mediated immune and inflammatory responses through several means, including cytokine secretion, reactive oxygen species formation, and activation of the ERK signaling pathway. 
LncRNA Dnm3os Macrophages Das et al. [133Alter global histone modifications, up-regulated inflammation, immune response genes and phagocytosis via binding with nucleolin and ILF-2 
LncRNA lethe Macrophages Miranda-Diaz et al. [135Eliminates the increased ROS production induced by high glucose conditions, while also attenuating the up-regulation of Nox2 expression 
SENCR Vascular smooth muscle cells Zou et al. [137Reverses the inhibitory effect of high glucose on the proliferation and migration of mouse vascular smooth muscle cells 
GAS5 Vascular smooth muscle cells Carter et al. [138A risk factor for diabetes 
  Wang et al. [139A potent regulator of endothelial and vascular smooth muscle cells function and contributes to hypertension-related remodeling of arteries, like renal arteries 

Abbreviations: SENCR, smooth muscle and endothelial cell-enriched migration/differentiation-associated lncRNA; VEGF, vascular endothelial growth factor.

To determine the expression pattern of lncRNAs in experimental DKD, kidney specimens collected from db/db mice were subjected to microarray analysis. In total, 311 lncRNAs were found to be differentially expressed between the db/db group and the control db/m group, of which 105 were significantly up-regulated and 206 were significantly down-regulated. In-depth analysis demonstrated that 147 lncRNAs were related to cis-regulation, and several groups of lncRNAs may participate in biological pathways related to DKD via trans-regulation of protein-coding genes [82]. These data are instrumental to identify potential candidate lncRNAs involved in DKD, though the complex functions and exact roles of these lncRNAs still wait to be unraveled.

The role of lncRNAs in diabetes-related renal parenchymal cell injury

Involvement of lncRNAs in diabetic podocytopathy

Podocytes are a key structural constituent of the glomerular filtration barrier that determines glomerular permeability to albumin and other plasma proteins in the circulation. The injury of podocytes has been considered as an important early pathologic event of DKD. Research on the relationship between lncRNA and podocyte injury is in the ascendant.

β-catenin, a key signaling transducer of the Wnt signaling pathway, has been known to contribute to podocyte injury in DN. MALAT1, an lncRNA extensively expressed in diverse mammalian tissues, was found to be dysregulated in streptozotocin (STZ)-induced DKD in murine models and also implicated in high glucose-induced podocyte damage in vitro via its interplay with β-catenin. MALAT1 knockdown by siRNA transfection rectified podocyte damage via abrogating SRSF1 overexpression, a MALAT1 lncRNA-binding protein, and in turn, reversed nuclear accumulation of β-catenin triggered by high glucose. In addition, β-catenin via its binding to the MALAT1 promotor region is capable of regulating MALAT1 levels, in agreement with a reciprocal feedback regulation between MALAT1 and β-catenin [83].

The lncRNA TUG1 has been implicated in metabolic alterations in podocytes in diabetic mice. TUG1 seems to be able to regulate the peroxisome proliferator-activated receptor γ (PPARγ) co-activator α (PGC-1α, encoded by Ppargc1a) and participate in the regulation of mitochondrial function in podocytes in a murine model of DKD [84,85]. Podocyte-specific overexpression of TUG1 by lentivirus-mediated gene transduction in diabetic mice improved the biochemical and renal histological changes associated with DKD, in support of a key role of this lncRNA in DKD.

Based on a microarray analysis of dysregulated lncRNAs in kidney tissues from db/db versus control mice, the lncRNAs Gm5524 and Gm15645 were identified to be the most significant ones. Gm5524 was prominently up-regulated, while Gm15645 was markedly down-regulated in the kidneys from db/db mice. In cultured mouse podocytes exposed to high ambient glucose, either knockdown of Gm5524 by siRNA or overexpression of Gm15645 by plasmids transfection could attenuate podocyte autophagy [86].

LINC01619 was found to be down-regulated in renal biopsy tissues from patients with DN, associated with proteinuria and impaired renal function. It is mainly expressed in podocyte cytoplasm and act as a ‘sponge’ for mir-27a. Decreased expression of LINC01619 could repress Foxo1 expression and thus activate ER stress in DN. In addition, LINC01619 is able to trigger oxidative stress and podocyte injuries, marked by increased podocyte apoptosis, diffused podocyte foot process effacement, and impaired renal function in diabetic rats in vivo. This effect was also reproduced in high glucose-treated podocytes in vitro [87].

Involvement of lncRNAs in diabetic endothelial injury

Capillary endothelial cells are the first to be exposed to diabetic milieu like hyperglycemia. As such, capillary endothelial injury is one of the characteristic pathologic changes of diabetes, as commonly seen in diabetic retinopathy and DKD [88]. Kidney glomerulus is virtually a complex capillary network and rich in endothelial cells. However, most of the previous studies on diabetic glomerulopathy focused on glomerular cells other than endothelial cells [89]. How glomerular endothelial cells (GECs) are injured in the setting of diabetes has been under investigated.

Recent evidence suggests that GEC damage is already present at the early phases of DKD prior to podocyte injury. GEC injury in diabetes is accompanied by structural abnormalities in the endothelium and is likely sufficient for the development and progression of DKD. In support of this view, genetic targeting of specific genes associated with endothelial injury, like endothelial NOS (eNOS), accelerates the development of DKD in mice [90]. However, the mechanism of GEC injury remains unclear during the early stage of DKD. Lately, there is evidence pointing to the involvement of lncRNAs.

The lncRNA MIAT and MALAT1 were found to be significantly up-regulated both in retinal endothelial cells exposed to high glucose and in renal tissues procured from diabetic mice and patients. Bioinformatics analysis and subsequent experimental validation indicated that MIAT interacts with mir-150-5p through a ceRNA mechanism and modulate endothelial expression of vascular endothelial growth factor (VEGF), which is critical for endothelial cell homeostasis via an autocrine or paracrine mode [91,92]. In contrast, in renal tubular epithelial cells (HK-2), high glucose treatment decreased MIAT expression, associated with a lower level of Nrf2, whereas overexpression of MIAT offset the high glucose repressed Nrf2 antioxidant response [93], denoting a beneficial effect of MIAT-regulated Nrf2 signaling axis. Of note, this effect is reminiscent of the GSK-3β regulated Nrf2 signaling that was lately unraveled in the kidney [94]. Whether MIAT is involved in GSK-3β signaling and how the cross-talk between MIAT and GSK-3β signaling impacts Nrf2 antioxidant response is worth further investigation. The disparate role of MIAT in retina and renal tubule cells is in line with the opinion that the same lncRNA may exert distinct effects in different cell types. These findings imply a potential involvement of MALAT1 in diabetic microvascular complications [95] and inhibition of MALAT1 could reduce migration and prevent proliferation in retinal endothelial cells exposed to high ambient glucose.

Involvement of lncRNAs in mesangiolysis and mesangial expansion

Excessive accumulation of ECM in the glomerulus is considered a hallmark of diabetic glomerulopathy and a key mechanism in the progression of glomerulosclerosis in DKD [96]. Mesangial cells are a specialized type of vascular smooth muscle cells (VSMC)/pericytes that wrap around the capillaries of the renal glomerulus. Mesangial cells are also the major source of glomerular ECM [97]. Therefore, inhibiting the proliferation of mesangial cells, and consequently the accumulation of ECM, may be a practical approach to treat or prevent DKD. LncRNAs also play an important role in mesangial cell proliferation and ECM accumulation [98,99].

In the aforementioned microarray profiling of lncRNA expression in renal tissues from db/db mice, CYP4B1-PS1-001 was one of the most significantly down-regulated lncRNA. This finding was further validated in cultured mouse mesangial cells under high glucose conditions. In contrast, lentivirus-mediated gene transduction of CYP4B1-PS1-001 attenuated the high glucose-induced proliferation of mouse mesangial cells as well as the expression of proliferating cell nuclear antigen and CyclinD1, which are both critical for cell cycle progression. CYP4B1-PS1-001 overexpression also diminished the overproduction of ECM components like fibronectin and collagen I, implying that CYP4B1-PS1-001 inhibits the proliferation and fibrosis in mesangial cells [100]. Other studies found that lncRNA ENSMUST00000147869 was down-regulated in mouse mesangial cells exposed to high ambient glucose. In addition, overexpression of ENSMUST00000147869 protected mouse mesangial cells from proliferation and fibrosis despite an unknown mechanism [27,101,102].

In an effort to understand the underlying mechanism for the association between the intergenic lncRNA PVT1 and ESRD due to T2DM as evidenced by the GWAS data [46,103], quantitation of PVT1-derived microRNAs was carried out in different types of kidney cells. The levels of mir-1207-5p were at least 100-fold higher compared with the other PVT1-derived miRNAs in normal human renal proximal tubule epithelial cells, podocytes and normal human mesangial cells. Mir-1207-5p overexpression by miRNA mimics increases the expression of a number of fibrogenic molecules in mesangial cells, including TGF-β1, PAI-1 and fibronectin [104]. These data suggest that both PVT1 and PVT1-derived microRNAs like mir-1207-5p are centrally involved in the complex pathogenesis of DN. As mentioned above, lncRNA TUG1 plays a key role in diabetic podocyte injury [84,85]. There is evidence that lncRNA TUG1 is able to act as an endogenous sponge of mir-377, which is known to be up-regulated in db/db mice [26,105]. TUG1 overrode the effect of mir-377 on suppressing PPARγ and inhibited the high glucose elicited expression of fibrogenic molecules, including PAI-1, TGF-β1, fibronectin and collagen IV [105].

Mechanistically, lncRNAs may be a downstream target or transmitter of TGF- β1 signaling, the master regulator of fibrosis. Indeed, there is evidence that TGF-β1 activates Akt in cultured mesangial cells by promoting the expression of mir-216a and mir-217, along with their host lncRNA, RP23, resulting in mesangial cell proliferation and hypertrophy [106]. Similarly, TGF-β1 is also able to induce the expression of mir-192 in mesangial cells, together with its host lncRNA, CJ241444, and in turn lead to Akt and p300 activation, resulting in mesangial hypertrophy [107]. Another lncRNA, which also could be induced by TGF-β1 or high glucose in cultured mesangial cells, is lnc-MGC [108]. Its relevance to DN was evidenced by the increased expression of lnc-MGC in the glomeruli of mouse models of DN. Lnc-MGC was regulated by the endoplasmic reticulum (ER) stress-related transcription factor, CHOP. Diabetic Chop−/− mice exhibit reduced expression of cluster microRNAs and lnc-MGC and, meanwhile, are protected from DN, underscoring a potential benefit of targeting lnc-MGC in controlling DN progression. In addition, the lncRNA ASncmtRNA-2 (antisense mitochondrial ncRNA-2) was up-regulated by reactive oxygen species and positively correlated with the expression of the profibrotic growth factor TGF-β1 and its target molecule, fibronectin, in vivo in diabetic mice kidneys and in vitro in high glucose-treated mesangial cells [109], suggesting that ASncmtRNA-2 may contribute to DKD via promoting glomerular fibrogenesis.

The lncRNA Erbb4-IR, located within the intron region between the first and second exon of mouse Erbb4 gene on chromosome 1, was one of the common Smad3-dependent lncRNAs. Expression of Erbb4-IR was specifically induced by AGEs via a Smad3-dependent mechanism, but not by high glucose. In db/db mice with DN, Erbb4-IR levels were significantly up-regulated in the kidney, and this effect was abolished in db/db littermates with Smad3 knockout [110]. Kidney-specific silencing of Erbb4-IR by lentivirus-mediated approach improved kidney histology and decreased albuminuria in db/db mice, in part due to suppression of TGF-β/Smad3 signaling, one of the crucial pathways promoting kidney fibrosis in DKD [111]. Additionally, the Erbb4-IR-mir-29b axis was likely a key mechanism of DN because Erbb4-IR was able to bind with the 3′ untranslated region of mir-29b genomic sequence to suppress mir-29b expression at transcriptional level. In contrast, silencing of renal Erbb4-IR increased mir-29b expression and thereafter protected against progressive renal injury in db/db mice [112].

Another lncRNA participating in DN pathogenesis via TGF-β is lncRNA NONHSAG053901. It was found that the expression of NONHSAG053901 was drastically elevated in both DN mouse model and cultured mesangial cells. Overexpression of NONHSAG053901 remarkably promoted inflammation, fibrosis and proliferation in MCs via direct binding to early growth response protein 1 (Egr-1). After knockdown of Egr-1, the the effects of NONHSAG053901 on stimulation of proinflammatory cytokines were abolished. These results together suggested that NONHSAG053901 promoted proinflammatory cytokines via stimulating Egr-1/TGF-β-mediated renal inflammation [113].

The lncRNA Gm6135 is also associated with DN in mouse models. Mechanistically, Gm6135 is able to augment the expression of toll-like receptor 4 (TLR4) by competitively binding to and sponging mir-203-3p and thereby promote mesangial proliferation [114], suggesting that Gm6135/mir-203/TLR4 axis played an important role in the pathogenesis of DN.

The lncRNA LINC00968 was highly expressed in the kidney in the diabetic db/db mice and also in high glucose-cultured mesangial cells. Inhibition of LINC00968 by siRNAs significantly inhibited mesangial cell proliferation and cell cycle progression in high glucose culture, and attenuated ECM accumulation (e.g. fibronectin, collagen IV). These effects were achieved by LINC00968-mediated epigenetic repression of wild-type p53-activated fragment 1 (WAF1) via recruiting Enhancer of Zeste Homolog 2 (EZH2) [115].

Central to inflammation in all kidney diseases including DKD is the activation of NF-κB signaling pathway. In agreement, much evidence has confirmed that NF-κB plays a key role in renal inflammation and fibrosis during the progression of DN. Recent data revealed that the NACHT, LRR and PYD domain-containing protein 3 (NLRP3) inflammasome directly participated in renal inflammatory processes following NF-κB activation, leading to the progression of diabetic glomerular damage, including mesangial proliferation and glomerulosclerosis [116,117]. The lncRNA Gm4419 has been predicted by bioinformatics analysis to associate with NF-κB. Subsequent studies confirmed that Gm4419 could activate the NF-κB pathway by directly interacting with the p50 subunit of NF-κB, which could interact with NLRP3 inflammasome in mesangial cells. Moreover, Gm4419 knockdown obviously inhibited the expressions of proinflammatory cytokines and biomarkers of renal fibrosis, and reduced cell proliferation in mesangial cells under high glucose condition. Conversely, overexpression of Gm4419 could increase the inflammation, fibrosis and cell proliferation in mesangial cells under normal glucose condition (Figure 3) [118].

LncRNAs involved in diabetes-related renal parenchymal cell injury
Figure 3
LncRNAs involved in diabetes-related renal parenchymal cell injury

Schematic diagram depicting the lncRNAs involved in diabetes-related injuries to diverse kidney parenchymal cells, including glomerular podocytes, GECs, glomerular mesangial cells and renal tubular epithelial cells.

Figure 3
LncRNAs involved in diabetes-related renal parenchymal cell injury

Schematic diagram depicting the lncRNAs involved in diabetes-related injuries to diverse kidney parenchymal cells, including glomerular podocytes, GECs, glomerular mesangial cells and renal tubular epithelial cells.

Involvement of lncRNAs in diabetic tubulopathy

Although glomerular lesions are unarguably of great importance and significance in DKD, diabetic tubular injury is also an essential component of DKD pathology and actually the major determinant of renal prognosis in diabetes [119]. Tubular cells have been demonstrated to be a key target of hyperglycemia-induced injury [120]. However, the exact mechanisms responsible for diabetic tubulopathy remains largely uncertain. Recently, there is evidence suggesting that lncRNAs are likely potential regulators of diabetic tubular injury in DKD [26,27,102].

In diabetic rats, the expression of MIAT was reduced and negatively correlated with serum creatinine and blood urea nitrogen levels [92,121]. In consistency, in cultured renal tubular epithelial HK-2 cells, the expression levels of MIAT and Nrf2 were lessened after exposure to high glucose. MIAT is able to enhance the Nrf2 stability and this is seemingly involved in DN by regulating proximal convoluted tubule cell viability [93].

Chronic tubulointerstitial hypoxia is one of the final common pathways to progress ESRD for all kidney diseases, including DN [122,123]. HIF-1 (hypoxia-inducible factor-1) is a master transcriptional factor regulated by hypoxia and targets numerous downstream genes. In human renal tubular HK-2 cells and primary rat renal proximal tubular cells exposed to hypoxia, RNA-seq identified 44 up-regulated lncRNAs to have physical interaction with HIF-1. Among these lncRNAs, a novel lncRNA, DARS-AS1 (aspartyl‐tRNA synthetase antisense 1), was found by CHIP-seq assay to contain two hypoxia-responsive elements and HIF-1 was able to bind to the promoter region of DARS-AS1. Knockdown of DARS-AS1 deteriorated apoptotic cell death triggered by hypoxia, suggesting an important role of DARS-AS1 in inhibiting apoptotic cell death of renal tubular cells [124].

In mice models of inspiratory hypoxia, MALAT1 expression was up-regulated in renal proximal tubular cells and knockdown of MALAT1 could reduce new tubule formation [95,125]. Similarly, in STZ-induced diabetic rats, MALAT1 expression was also substantially increased in renal tubular epithelial cells but mir-23c, a target of MALAT1, was decreased. This finding was reproduced in high glucose-treated HK-2 cells. Mir-23c is able to directly repress the expression of the RNA-binding protein ELAVL1 and thereby decrease the expression of the inflammasome NLRP3. As such, lncRNA MALAT1 contributes to NLRP3-mediated renal tubular epithelial apoptosis by controlling the mir-23c-modulated ELAVL1 expression in DN [126].

Role of lncRNAs in other pathogenic mechanisms accounting for DKD

Macrophage and inflammation

Increasing evidence suggests that inflammation is involved in the progression of diabetic complications. Proinflammatory cytokines and inflammatory cells constitute a complex regulatory network that promotes chronic inflammation and kidney destruction in DKD [127–129]. Therefore, investigating the mechanism of inflammation caused by diabetes and developing novel anti-inflammatory strategies may provide new approaches to the treatment of DKD. However, the relationship between lncRNAs and renal inflammation in DKD is still obscure.

Numerous studies have suggested that macrophage infiltration and activation in the diabetic kidney contribute to DKD. The impact of diabetes on genome-wide lncRNA expression has been studied in macrophages. Differential expression analysis of lncRNAs in macrophages isolated from diabetic mice and patients revealed IR143HG, the human homolog of mouse E330013P06, was the lncRNA that most significantly increased. Additionally, both mouse E330013P06 and human MIR143HG are host genes for mir-143 and mir-145. Overexpression of E330013P06 in RAW 264.7 macrophages up-regulated the expression of a number of proinflammatory and proatherogenic genes that were instigated by high glucose treatment, whereas knockdown of E330013P06 could lead to the opposite outcome [130]. These findings imply that lncRNA E330013P06 and MIR143HG could serve as a novel therapeutic target to attenuate inflammation in diabetes.

P2X7 receptors (P2X7Rs) are members of the family of ionotropic ATP-gated receptors. Increased expression of P2X7 receptors in peripheral blood monocytes may alter the innate immunity [131]. It was found that treating RAW264.7 macrophage cells with high glucose and high plasma free fatty acids could increase the expression of lncRNA uc.48+ and provoke P2X7R–mediated immune and inflammatory responses through several means, including cytokine secretion, reactive oxygen species formation, and activation of the ERK signaling pathway. The uc.48+ specific siRNA diminished inflammation factors and thus influenced the course and outcome of the immune and inflammatory responses [132].

A recent study demonstrated that the lncRNA Dnm3os or dynamin 3 opposite strand, which has nuclear localization and chromatin enrichment, is up-regulated in monocytes from type 2 diabetic patients relative to controls. Similar findings were also made in bone marrow-derived macrophages of type 2 diabetic db/db mice, diet-induced insulin-resistant mice, diabetic ApoE−/− mice and cultured mouse and human macrophages under diabetic conditions (high glucose and palmitic acid). The increased expression of Dnm3os resulted from NF-κB activation in macrophages under diabetic conditions, and this altered global histone modifications and up-regulated inflammation, immune response genes and phagocytosis via binding to nucleolin and interleukin enhancer-binding factor 2. These findings may lead to new lncRNA-based therapies for inflammatory DM complications [133].

Oxidative stress

Diabetic milieu consisting of persistent hyperglycemia, AGE and cellular hypermetabolism and hypertrophy inevitably lead to ROS overproduction and oxidative stress both systemically and locally in the kidney. Even a slight increase in ROS above the physiological range can cause significant conformational changes in the lipids, proteins, carbohydrates and nucleic acids, resulting in significant impairment of cellular function and structure. Oxidative stress in DN could act as a trigger, modulator and link within the complex web of pathological events that occur in DN [134]. Oxidative stress is highly associated with the development and progression of DKD. ROS scavengers are sufficient to attenuate diabetic kidney injury. As shown by emerging evidence, lncRNAs are involved in oxidative stress in diabetes. In cultured murine RAW macrophages, exposure to high glucose conditions significantly induced ROS production and nox2 gene expression, but markedly decreased the expression of the lncRNA Lethe. Ectopic overexpression of Lethe in RAW cells attenuated nox2 up-regulation and ROS overproduction induced by high glucose conditions. Similar findings were also made in primary bone marrow-derived macrophages prepared from diabetic mice. These findings provide the first evidence that lncRNA Lethe is involved in the regulation of ROS production in macrophages through modulation of nox2 gene expression possibly via regulating NF-κB signaling [135].

Diabetic vascular injury and hypertension

As a result of diabetic vascular injury, arterial hypertension is common in patients with diabetes and in turn it is a major determinant driving the development and progression of DN. The Americans with Disabilities Act (ADA) guidelines focuses on the objective to achieve systolic arterial pressures of <130  mmHg and diastolic arterial pressures of <80  mmHg in order to decrease proteinuria and slow progression of the DN [134,136]. Emerging studies find that lncRNAs are dysregulated in diabetic vascular injury and associated with hypertension. Emerging evidence suggests that lncRNAs is capable of regulating the pathophysiological process of diabetic vascular injury.

Smooth muscle and endothelial cell-enriched migration/differentiation-associated lncRNA (SENCR) is a vascular cell-enriched lncRNA, which was found to be down-regulated in T2DM db/db mice and also in vitro in VSMC exposed to high glucose. Studies showed that SENCR could promote the proliferation and migration of VSMC via regulation of Foxo1 and transient receptor potential cation channel 6. Ectopic overexpression of SENCR abrogated the inhibitory effect of high glucose on the proliferation and migration of mouse VSMC [137]. More studies are required to provide direct evidence supporting the role of SENCR in diabetic vascular injury.

Circulating levels of the lncRNA GAS5 have been shown to associate with T2DM in a cohort of U.S. military veterans, denoting GAS5 as a risk factor for diabetes [138]. Interestingly, GAS5 is mainly expressed in endothelial cells and VSMC and its expression is significantly obliterated in hypertension. Mechanistically, GAS5 is likely a potent regulator of endothelial cell and VSMC function and is involved in hypertension-related remodeling of arteries, like renal arteries. These findings suggest that GAS5 as a critical regulator in hypertension and demonstrated the potential of gene therapy and drug development for treating hypertension [139]. Whether GAS5 is associated with the development or progression of DKD merits further investigation.

Conclusion

The mechanism underlying DKD is highly complex and may involve multiple components, including parenchymal kidney cell injury, renal inflammation and extra-renal factors. While lifestyle changes may be of some help at the early phase of T2DM, treatment of diabetes-related complications like DKD relies mainly on medical therapies. The existing therapeutic modalities for DKD are of limited efficacy in retarding the progression of DKD and may pose a significant risk of adverse effects. To address this unmet need, many efforts have been dedicated to explore the mechanisms further accounting for DKD and identify novel therapeutic targets.

In parallel with the advances in biotechnology, lncRNAs, which were assumed to be the ‘nonsense and dark materials of the genome’, have been recently demonstrated to play pivotal roles in all pathobiological processes involved in DKD, including diabetic tubulopathy and diabetic glomerulopathies, like podocytopathy, endothelial dysfunction, mesangiolysis and mesangial expansion. Compared with other RNAs, lncRNAs are less abundant and evolutionarily less conserved. However, it seems unique for lncRNAs to be highly tissue-specific in terms of their biological activities. To this end, the same lncRNA may exert distinct functions in different cell types and contribute to DKD. To name a few, MALAT1 is commonly expressed in glomerular podocytes, renal tubular cells and macrophages, but involved in different pathogenic processes leading to DKD. This unique characteristic also applies to other lncRNAs like TUG1 and PVT1. On the contrary, different lncRNAs may exert a similar cellular effect through the same signaling mechanism. For instance, PVT1, TUG1, RP23, MGC and ASncmtRNA2 all contribute to ECM accumulation in DKD through targeting TGF-β1 pathway. ANRIL, AScmtRNA, H19, HOTAIR, MALAT1, which play vital roles in different cells or tissues, all have emerged as potent regulators of ROS production in mitochondrial metabolism. This unique feature of tissue specific action may well prepare lncRNAs to serve as novel candidate biomarkers for the early diagnosis or prognosis of DKD.

Therapeutic targeting of lncRNAs for the prevention or treatment of DKD in human patients seems underdeveloped and immature at the current stage but is promising and feasible in the future thanks to the latest breakthroughs in the biotechnology of gene therapy. To date, at least in preclinical studies, there are mainly four approaches to change the expressions or functions of lncRNAs: 1) RNAi technology. lncRNA levels can be inhibited by using RNAi. There have been a number of clinical trials for siRNA-based therapeutics are ongoing, particularly for the treatment of cancers [140]. 2) Antisense oligonucleotides (ASOs) and locked nucleic acid GapmeRs, which can mitigate lncRNA activity or induce enzyme-mediated degradation, respectively. 3) Highly selective small molecule inhibitors, which can intercept the molecular interactions between lncRNAs and their binding molecules and thereby block the function of lncRNAs. 4) Disruption of secondary structure of targeting lncRNAs [141]. Subcellular distribution of lncRNA is a key determinant that affects the efficacy of knock down by nucleic acid-based therapeutic approaches. ASOs will more effectively suppress nuclear lncRNAs, while siRNAs and GapmeRs strongly affect cytoplasmic lncRNAs. As such, the choice of a proper modality to perturb a lncRNA will depend on the molecular and physical characteristics of the specific lncRNA.

In summary, accumulating evidence in support of the role of lncRNAs in the pathogenesis of diabetes and DKD has paved the way for developing novel therapeutic strategies based on targeting lncRNAs and for strengthening our understanding of the molecular mechanisms of these common diseases. Moreover, RNA-based therapeutics is in the ascendant and may represent a promising strategy for personalized and precision treatment of DKD, by which the activity of specific protective and pathogenic lncRNAs may be manipulated via introducing respective gain- and loss-of-function mutants according to a patient’s genetic profile. Additionally, the unique tissue-specific characteristics of lncRNAs may be harnessed to develop certain lncRNAs into the next generation biomarkers for early diagnosis/prognosis of diabetes and DN. However, a number of challenges still need to be addressed to achieve these goals and the most urgent one is to translate the preclinical data and observations into clinical application.

Availability of data and material

Data for this review were collected through Pubmed. The following search terms were used: long noncoding RNA, lncRNA, diabetes, DKD, DN, podocytes, glomerulus, mesangial cells, renal tubular cells, inflammation, pathogenesis, and treatment. Only articles published in English were included.

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Funding

This work was supported in part by the Natural Science Foundation of China [grant numbers U1604284, 81670663 and 81770672].

Author Contribution

Z.L. devised the conceptual ideas. J.G. performed the literature search and drafted the original manuscript. J.G. drew the figures. R.G. contributed to revision. All authors approved the final version of the manuscript.

Abbreviations

     
  • AGE

    advanced glycation-end product

  •  
  • ANRIL

    antisense noncoding RNA in the INK4 locus

  •  
  • ApoE-/-

    apolipoprotein E-deficient

  •  
  • ASO

    antisense oligonucleotide

  •  
  • DARS-AS1

    aspartyl‐tRNA synthetase antisense 1

  •  
  • Cdkn2a

    Cyclin-dependent kinase inhibitor 2a

  •  
  • ceRNA

    competing endogenous RNA

  •  
  • ChIP

    chromatin immunoprecipitation

  •  
  • DKD

    diabetic kidney disease

  •  
  • dlk1

    δ-like non-canonical notch ligand 1

  •  
  • DM

    diabetes mellitus

  •  
  • DN

    diabetic nephropathy

  •  
  • ECM

    extracellular matrix

  •  
  • ELAVL1

    embryonic lethal, abnormal vision, drosophila-like 1

  •  
  • ESRD

    end-stage renal disease

  •  
  • FOXO1

    forkhead box O1

  •  
  • GAS5

    growth arrest-specific transcript 5

  •  
  • GEC

    glomerular endothelial cell

  •  
  • GWAS

    genome-wide association study

  •  
  • HIF-1

    hypoxia-inducible factor-1

  •  
  • HOTTIP

    HOXA distal transcript

  •  
  • IFN-γ

    interferon-gamma

  •  
  • IGF2-AS

    insulin-like growth factor 2 antisense RNA

  •  
  • Igf2

    insulin-like growth factor 2

  •  
  • IGF-1

    insulin-like growth factor-1

  •  
  • IL-1β

    interleukin 1 beta

  •  
  • JNK

    c-Jun NH2-terminal kinase

  •  
  • Kcnq1

    potassium voltage-gated channel subfamily q member 1

  •  
  • lincRNA

    long intergenic noncoding RNA

  •  
  • lncRNA

    long non-coding RNA

  •  
  • lncRNA ASncmtRNA-2

    antisense mitochondrial non-coding RNA-2

  •  
  • LRR

    leucine-rich repeat

  •  
  • MafA

    fibrosarcoma oncogene homolog A

  •  
  • MALAT1

    metastasis-associated lung adenocarcinoma transcript 1

  •  
  • MEG3

    maternally expressed mouse gene 3

  •  
  • MIAT

    myocardial infarction associated transcript

  •  
  • NACHT

    NAIP, CIITA, HET-E and TEP1 domain

  •  
  • ncRNA

    non-coding RNA

  •  
  • NEAT1

    nuclear paraspeckle abundant transcript 1

  •  
  • NLRP3

    NACHT, LRR and PYD domain-containing protein 3

  •  
  • Nrf2

    nuclear factor erythroid 2-related factor 2

  •  
  • PAI1

    plasminogen activator inhibitor 1

  •  
  • pancRNA

    promoter-associated non-coding RNA

  •  
  • Pdx1

    pancreatic and duodenal homeobox 1

  •  
  • PINK1

    PTEN-induced kinase 1

  •  
  • PPARγ

    peroxisome proliferator-activated receptor γ

  •  
  • PVT1

    plasmacytoma variant translocation 1

  •  
  • PYD

    pyrin domain

  •  
  • RAAS

    renin–angiotensin–aldosterone system

  •  
  • ROS

    reactive oxygen species

  •  
  • SENCR

    smooth muscle and endothelial cell-enriched migration/differentiation-associated long noncoding RNA

  •  
  • SNP

    single nucleotide polymorphism

  •  
  • SRA

    steroid receptor RNA activator

  •  
  • SRSF1

    serine/arginine-rich splicing factor 1

  •  
  • STAT3

    signal transducer and activator of transcription 3

  •  
  • STZ

    streptozotocin

  •  
  • T1DM

    type 1 DM

  •  
  • T2DM

    type 2 DM

  •  
  • TGF-β1

    transforming growth factor beta 1

  •  
  • TLR4

    toll-like receptor 4

  •  
  • TUG1

    taurine-upregulated gene 1

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