Diverse aetiologies result in significant deviation from homoeostasis in the kidney, leading to CKD (chronic kidney disease). CKD progresses to end-stage renal disease principally as a result of renal fibrosis, although the molecular mechanisms underlying this fibrotic process are still poorly understood. miRNAs (microRNAs) are a recently discovered family of endogenous short single-stranded RNAs that regulate global gene expression at the post-transcriptional level. The recent findings from our laboratory and others discussed in the present review outline pleiotropic roles for miR-192 in renal homoeostasis and in the fibrotic kidney. We describe miR-192-driven anti-and pro-fibrotic effects via the repression of ZEB1 and ZEB2 (zinc finger E-box-binding homeobox proteins 1 and 2), resulting in changes in extracellular matrix deposition and cell differentiation.

Renal miRNA (microRNA) expression

The miRNA family of endogenous short single-stranded RNAs down-regulate gene expression post-transcriptionally. Sequence-specific miRNA binding at recognition sites in the 3′-UTRs (untranslated regions) of target mRNAs leads to translational repression and/or mRNA destabilization via mechanisms that are not yet fully defined. miRNA expression contributes significantly to the definition of cell phenotype, and since miR-34a, miR-192, miR-194, miR-203 and miR-450 are expressed preferentially in the renal cortex, they are of particular potential relevance to cell biology in the kidney [13]. Figure 1(A) depicts human genomic loci 1q41 and 11q13.1, from which cluster partners miR-194-1/miR-215 and miR-194-2/miR-192 respectively, are transcribed. For miR-194-2/miR-192, the genomic regions corresponding to the primary (pri-), pre- and mature miRNA sequences are highlighted, and the mature miRNA sequences are given. The two miR-194 isoforms are processed to the same mature sequence by mechanisms that are discussed below. Aligned mature nucleotide sequences for each miRNA are also shown. miR-192 and miR-215 have the same seed sequence and are therefore likely to target the same mRNAs. The expression of both of these miRNA clusters is therefore considered in the present review.

Cluster organization of human miR-192, miR-194 and miR-215, and physiology of the renal nephron

Figure 1
Cluster organization of human miR-192, miR-194 and miR-215, and physiology of the renal nephron

(A) Human miR-192 is co-transcribed at 11q13.1 with cluster partner miR-194-2; both miR-194-1 and miR-215 transcripts are processed from 1q41. Nucleotide sequences for mature miR-192, miR-194 and miR-215 are shown, with variants from the miR-192 sequence emboldened and seed sequences underlined. All sequences are depicted in 5′→3′ orientation. (B) The main features of the nephron include the proximal convoluted tubule, the source of PTCs, and the glomerulus, from where mesangial cells and podocytes are derived.

Figure 1
Cluster organization of human miR-192, miR-194 and miR-215, and physiology of the renal nephron

(A) Human miR-192 is co-transcribed at 11q13.1 with cluster partner miR-194-2; both miR-194-1 and miR-215 transcripts are processed from 1q41. Nucleotide sequences for mature miR-192, miR-194 and miR-215 are shown, with variants from the miR-192 sequence emboldened and seed sequences underlined. All sequences are depicted in 5′→3′ orientation. (B) The main features of the nephron include the proximal convoluted tubule, the source of PTCs, and the glomerulus, from where mesangial cells and podocytes are derived.

miR-192 expression and pleiotropic function in the kidney

Anti-fibrotic miR-192 function in human renal biopsies and human and mouse proximal tubular cells

Figure 1(B) illustrates key compartments of the nephron. These include the renal proximal tubule, from where epithelial PTCs (proximal tubular cells) are derived, and the glomerulus, the source of mesangial cells and podocytes. We have demonstrated down-regulated miR-192 expression in renal biopsies from advanced diabetic nephropathy patients, together with a correlation between low miR-192 expression and structural (tubulointerstitial fibrosis) and functional (reduced estimated glomerular filtration rate) indicators of renal damage [4]. Our laboratory has also shown that incubation of human renal PTCs with TGF-β1 (transforming growth factor β1) in vitro decreased miR-192 expression [4]. Enforced miR-192 expression in PTCs down-regulated ZEB1 and ZEB2 (zinc finger E-box-binding homeobox proteins 1 and 2), and thus opposed TGF-β1-mediated suppression of E-cadherin expression (summarized in Figure 2A), a key early step in TGF-β1-mediated renal fibrogenesis [4]. Down-regulation of miR-192 by TGF-β1 in PTCs and in kidneys from diabetic apoE (apolipoprotein E)-deficient mice and rat PTCs has also been reported by Wang et al. [5], and linked to TGF-β1-mediated repression of E-cadherin (Figure 2B).

TGF-β1-driven miR-192 expression pathways in the kidney

Figure 2
TGF-β1-driven miR-192 expression pathways in the kidney

(A) Anti-fibrotic miR-192 function in human PTC. (B) Anti-fibrotic miR-192 function in rat PTCs. (C) Pro-fibrotic miR-192 function in mouse mesangial cells. (D) Pro-fibrotic miR-192 function in rat PTCs. CTGF, connective tissue growth factor.

Figure 2
TGF-β1-driven miR-192 expression pathways in the kidney

(A) Anti-fibrotic miR-192 function in human PTC. (B) Anti-fibrotic miR-192 function in rat PTCs. (C) Pro-fibrotic miR-192 function in mouse mesangial cells. (D) Pro-fibrotic miR-192 function in rat PTCs. CTGF, connective tissue growth factor.

Pro-fibrotic miR-192 function in the mesangial cells of the mouse renal glomerulus and rat PTCs

Work from Kato et al. [6] on mouse mesangial cells has shown that TGF-β1 increases miR-192 expression, and that repression of ZEB1 and ZEB2 expression by miR-192 facilitates collagen synthesis, enhancing matrix deposition and glomerulosclerosis [6] (Figure 2C). Additional downstream pathways in mesangial cells by which increased miR-192 expression may contribute to glomerulosclerosis have also been identified, including TGF-β1 auto-induction and Akt activation [7,8]. This group has also shown that inhibition of miR-192 in streptozotocin-induced diabetic mice reduced proteinuria [9]. Additionally, Chung et al. [10] showed miR-192 up-regulation by TGF-β1 in rat PTCs via a Smad3-dependent mechanism (Figure 2D).

The above studies point to an apparent divergence in the effects of miR-192-mediated repression of ZEB1 and ZEB2 proteins in PTCs compared with mesangial cells. TGF-β1-directed loss of E-cadherin expression is linked to loss of epithelial phenotype in carcinogenesis and in fibrosis in diverse tissues [11,12]. E-box-repressor proteins, including Snail1, Snail2, ZEB1 and ZEB2 have a clearly defined role in transcriptional repression of E-cadherin in these contexts. They are targeted by miRNAs from the miR-192 and miR-200 families, members of which are linked to loss of epithelial phenotype in fibroproliferative disorders [4,5,13] and cancer [1416]. In mesangial cells, however, ZEB1 and ZEB2 suppress collagen synthesis, and increased expression of miR-192 is linked to enhanced matrix deposition and glomerulosclerosis [6]. Furthermore, repression of miR-192 with locked nucleic acid-modified inhibitors leads to improved outcome in mouse models of kidney disease secondary to ureteric obstruction and diabetes [9]. Thus there are key differences in response to altered miR-192 expression in the various highly specialized cell lineages comprising the nephron. The additional targets, functions and the regulation of miR-192 in pathological and physiological contexts are therefore important areas for further study.

Regulation of miR-192 and miR-194 expression in the kidney and renal fibrosis

miR-192 clearly has fundamental functional importance in key aspects of renal biology and to the maintenance of cell function throughout the nephron. The nephron's response to physiological and pathological perturbations will therefore be influenced significantly by the regulation of miR-192 expression.

miRNA processing

RNA polymerase II processes pri-miRNAs (primary miRNAs) from their respective genomic loci, where their transcription is regulated by the mechanisms governing expression of the protein encoding mRNAs with which pri-miRNAs are frequently co-transcribed. The RNase-III enzyme Drosha processes pri-miRNAs to one or more pre-miRNA hairpin precursors in the nucleus. Dicer, another RNase III, processes pre-miRNAs to the miRNA duplexes of approximately 22 nucleotides in length from which the mature and bioactive miRNAs are derived, following cytoplasmic export [1719].

Genomics of miR-192, miR-194 and miR-215

As shown in Figure 1(A), miR-192 is co-transcribed with cluster partner miR-194-2 at 11q13.1. The pri-miR-194-2/192 sequence is located in intron 2 of splice-variant transcripts AB429223 and AB429224 at 11q13.1 (see AB429224, Figure 3A). The initiation site for the transcription of these sequences was defined previously by 5′-RACE (rapid amplification of cDNA ends) analysis [20].

Genomic organization and evolutionary conservation data for human miR-192, miR-194 and miR-215

Figure 3
Genomic organization and evolutionary conservation data for human miR-192, miR-194 and miR-215

(A) At 1q13.1, miR-194-2 and miR-192 are co-transcribed from the second intron of transcript AB429224, downstream of ATG2A. (B) Cluster partners miR-194-1 and miR-215 are encoded by the opposite genomic DNA strand to intron 12 of the human IARS2 gene. Gene symbols are shown and explained in full in the text. Data were obtained from http://genome.ucsc.edu/.

Figure 3
Genomic organization and evolutionary conservation data for human miR-192, miR-194 and miR-215

(A) At 1q13.1, miR-194-2 and miR-192 are co-transcribed from the second intron of transcript AB429224, downstream of ATG2A. (B) Cluster partners miR-194-1 and miR-215 are encoded by the opposite genomic DNA strand to intron 12 of the human IARS2 gene. Gene symbols are shown and explained in full in the text. Data were obtained from http://genome.ucsc.edu/.

Isoform 194-1 is transcribed from chromosome 1 together with its cluster partner miR-215 (Figure 1A). In contrast with the miR-194-2/192 locus, the miR-194-1/215 transcriptional unit is located on the opposite genomic strand to intron 12 of the IARS2 (isoleucyl-tRNA synthetase 2, mitochondrial) nuclear gene encoding mitochondrial protein (Figure 3B). This miRNA pair lies on the same strand and approximately central to a 60 kb intergenic gap between the transcription termination site of the RAB3CAP2 [RAB3 GTPase-activating protein subunit 2 (non-catalytic)] gene, and the transcription initiation site of the BPNT1 [3′(2′),5′-bisphosphate nucleotidase 1] gene (data available when zooming out from Figure 3B).

Figure 3 shows extensive evolutionary conservation of both miRNA pairs in mammals, with some evidence for sequences similar to the miR-194-1 cluster in the frog (Figure 3B) that is not evident for its isoform (Figure 3A).

Regulation of anti-fibrotic miR-192 function in human PTCs

In human PTCs, we have shown that synthesis of pri-miR-194-2/192 is down-regulated in the presence of TGF-β1 [21]. We have also demonstrated that transcriptional regulation of this precursor of mature miR-194-2 and miR-192 is mediated by HNF (hepatocyte nuclear factor) and p53 binding at their shared promoter region, upstream of the AB429223/4 transcription start site [21] (see Figure 3A). HNF binding at this promoter was decreased by TGF-β1, and decreased mature miRNA transcript levels followed HNF siRNA (short interfering RNA) knockdown [21].

Loss of PTC epithelial phenotype is associated with E-box repressor expression of Snail1, Snail2, ZEB1 and ZEB2. miR-192 targets the latter two repressors, and EMT (epithelial–mesenchymal transition) occurs as a result of down-regulation of miR-192 expression [4,5] (Figure 2A). Together with miR-200 family members, miR-192 also opposes ZEB-driven EMT downstream of p53 [13,22].

Regulation of pro-fibrotic miR-192 function in rat PTCs

TGF-β1 activates Smad3, which has been reported to bind at two AB429223/4 promoter sites (Figure 2D), although increased binding was not seen in the presence of TGF-β1 [10]. Chung et al. [10] suggested that one of these Smad-binding sequences was conserved in some eukaryotes. However, this observation may be due to the site's location within the 3′-UTR of the human ATG2A [ATG2 autophagy-related 2 homologue A (Saccharomyces cerevisiae)] gene and respective murine orthologues [21] (Figure 3A).

Significance of miR-192 pleiotropy in renal health and disease

miR-192 and HNFs

Our data have shown that expression of the pri-miR-194-2/192 transcript is controlled by p53 and HNF transcription factor binding, leading to co-expression of miR-192 with miR-194. miR-194 is linked to intestinal epithelial differentiation and is a marker of hepatic epithelial cells [20,23], but its potential roles in renal physiology and pathology are currently undetermined. Previous studies highlight other instances of co-ordinated expression of miRNAs transcribed from single contiguous polycistronic primary transcripts [24]. For instance, the miR-17-92 cluster yields six mature miRNAs, exhibiting cell-type/context-dependent functional pleiotropy during tumorigenesis [25].

We have identified HNFs as key regulators of miR-192 and miR-194 transcription, and suggested that miR-192 and miR-194 were effectors of HNF renal function. HNFs play fundamental roles in development and tissue homoeostasis [26,27] and, in the kidney, HNF-1α and HNF-4α are expressed in PTCs, whereas expression of HNF-1β occurs in the tubular epithelial cells of all nephron segments, and the collecting ducts [26,27]. HNF-1α and HNF-1β recognize the consensus sequence 5′-GTTAATNATTAAAC-3′ and bind to DNA as a homo- or hetero-dimer. Neither HNF-1α nor HNF-1β is expressed in cells of the glomerulus, including mesangial cells and podocytes [26], and this may account for cell-specific transcriptional regulation of miR-192 and miR-194.

Mutations in the genomic sequences encoding HNF-1α, HNF-1β and HNF-4α result in monogenic types of maturity-onset diabetes of the young, renal cysts and diabetes syndrome [26,28]. HNF-1α-knockout mouse kidneys have normal morphology, but the animals develop glucosuria and phosphaturia due to reduced sodium/glucose transporter and sodium/phosphate transporter (NPT1 and NPT2 respectively) expression [26]. HNF-1β-knockout mice are not viable and die before renal organogenesis [26].

miR-192, p53 and cell cycle

Our data also indicate that p53 binding is important in pri-miR-194-2/192 transcription in PTCs. p53 has recently been identified as a key transcriptional regulator of miR-192, miR-194 and miR-215 in plasma cells, and, additionally, these miRNAs are important downstream effectors of p53 function [29]. Validated targets of these miRNAs include the G1/G2 checkpoint proteins BCL2 (B-cell lymphoma 2), CDC7 (cell division cycle 7), MAD2L1 (mitotic arrest-deficient-2-like 1) and CUL5 (cullin 5) [30], and also MDM2 (murine double minute 2), a negative regulator of p53 [29].

Expression of miR-192, miR-194 and miR-215 therefore prevents p53 degradation, increasing activity of p53 and its other downstream targets, including CDKNA1 (cyclin-dependent kinase inhibitor 1A), p21 and p27 [29]. Ultimately, the expression of miR-192, miR-194 and miR-215 may trigger G1 and G2 cell-cycle arrest in a p53-dependent manner [2934]. p53 expression is linked to terminal differentiation of cells in the kidney and elsewhere [35,36]. We speculate that one mechanism by which p53 acts to control proliferation and maintain differentiation in renal epithelial cells is via miR-192 and miR-194. The roles of p53 and the HNFs may combine in the control of cell cycle, as recent results show that overexpression of HNF-1α in hepatocellular carcinoma cells re-establishes the expression of miR-192 and miR-194, with an increase in p21 and induction of G2/M arrest [37].

Cell-lineage-specific miR-192 effects

As illustrated in Figure 2, whereas several studies show decreased miR-192 expression in various renal pathologies and models [4,5,3840], several others show increases in miR-192 [6,10,4144]. In PTCs, TGF-β1-mediated decreased miR-192 facilitates expression of its targets ZEB1 and ZEB2, and hence loss of the key epithelial marker E-cadherin [4]. In mesangial cells, in contrast, TGF-β1 increases miR-192 expression, and the resultant repression of ZEB1 and ZEB2 enables expression of pro-fibrotic genes including collagens and mesangial cell hypertrophy [68]. This suggests that there may be lineage-specific variation in the control of miR-192 expression, and that elucidating the mechanisms that control miR-192 expression in mesangial cells may highlight important differences from PTCs. Cell-phenotype – and context-dependent transcriptional responses to TGF-β1 are well recognized, and have recently been linked to combinatorial interactions of Smad and HNF proteins [45]. TGF-β1 is also known to regulate HNF/DNA binding independent of HNF expression, via binding of phosphorylated Smad proteins to HNFs downstream of active TGF-β1 receptor complexes [46].

A more complete understanding of the role of miR-192 in renal physiology and disease may also require future studies examining expression in different nephron segments in vivo, and consideration of the full range of miR-192 targets, which is known to include regulators of circadian rhythm [47], cell cycle [29,30,32] and the WNK1 lysine-deficient protein kinase 1 [48]. In the distal nephron, miR-192 targets WNK1, leading to enhanced sodium excretion, and aldosterone-driven miR-192 down-regulation leads to sodium retention [48].

Concluding remarks

In summary, miR-192 has multiple important effects in the kidney with pleiotropy dependent of cell phenotype. Elucidating the molecular mechanism underpinning these effects will aid our understanding of renal physiology and pathology. miR-194 is co-transcribed with miR-192 and miR-215; however, its function and targets in the kidney are currently undetermined.

RNA UK 2012: An Independent Meeting held at The Burnside Hotel, Bowness-on-Windermere, Cumbria, U.K., 20–22 January 2012. Organized and Edited by Raymond O'Keefe and Mark Ashe (Manchester, U.K.).

Abbreviations

     
  • ATG2A

    ATG2 autophagy-related 2 homologue A (S. cerevisiae)

  •  
  • EMT

    epithelial–mesenchymal transition

  •  
  • HNF

    hepatocyte nuclear factor

  •  
  • IARS2

    isoleucyl-tRNA synthetase 2, mitochondrial

  •  
  • miRNA

    microRNA

  •  
  • pri-miRNA

    primary miRNA

  •  
  • PTC

    proximal tubular cell

  •  
  • TGF-β1

    transforming growth factor β1

  •  
  • UTR

    untranslated region

  •  
  • ZEB

    zinc finger E-box-binding homeobox protein

Funding

This work was supported by Kidney Research UK [grant number RP24/2009].

References

References
1
Bhatt
K.
Mi
Q.S.
Dong
Z.
microRNAs in kidneys: biogenesis, regulation, and pathophysiological roles
Am. J. Physiol. Renal Physiol.
2011
, vol. 
300
 (pg. 
F602
-
F610
)
2
Sun
Y.
Koo
S.
White
N.
Peralta
E.
Esau
C.
Dean
N.M.
Perera
R.J.
Development of a micro-array to detect human and mouse microRNAs and characterization of expression in human organs
Nucleic Acids Res.
2004
, vol. 
32
 pg. 
e188
 
3
Tian
Z.
Greene
A.S.
Pietrusz
J.L.
Matus
I.R.
Liang
M.
MicroRNA-target pairs in the rat kidney identified by microRNA microarray, proteomic, and bioinformatic analysis
Genome Res.
2008
, vol. 
18
 (pg. 
404
-
411
)
4
Krupa
A.
Jenkins
R.
Luo
D.D.
Lewis
A.
Phillips
A.
Fraser
D.
Loss of microRNA-192 promotes fibrogenesis in diabetic nephropathy
J. Am. Soc. Nephrol.
2010
, vol. 
21
 (pg. 
438
-
447
)
5
Wang
B.
Herman-Edelstein
M.
Koh
P.
Burns
W.
Jandeleit-Dahm
K.
Watson
A.
Saleem
M.
Goodall
G.J.
Twigg
S.M.
Cooper
M.E.
Kantharidis
P.
E-cadherin expression is regulated by miR-192/215 by a mechanism that is independent of the profibrotic effects of transforming growth factor-β
Diabetes
2010
, vol. 
59
 (pg. 
1794
-
1802
)
6
Kato
M.
Zhang
J.
Wang
M.
Lanting
L.
Yuan
H.
Rossi
J.J.
Natarajan
R.
MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-β-induced collagen expression via inhibition of E-box repressors
Proc. Natl. Acad. Sci. U.S.A.
2007
, vol. 
104
 (pg. 
3432
-
3437
)
7
Kato
M.
Arce
L.
Wang
M.
Putta
S.
Lanting
L.
Natarajan
R.
A microRNA circuit mediates transforming growth factor-β1 autoregulation in renal glomerular mesangial cells
Kidney Int.
2011
, vol. 
80
 (pg. 
358
-
368
)
8
Kato
M.
Putta
S.
Wang
M.
Yuan
H.
Lanting
L.
Nair
I.
Gunn
A.
Nakagawa
Y.
Shimano
H.
Todorov
I.
Rossi
J.J.
Natarajan
R.
TGF-β activates Akt kinase through a microRNA-dependent amplifying circuit targeting PTEN
Nat. Cell Biol.
2009
, vol. 
11
 (pg. 
881
-
889
)
9
Putta
S.
Lanting
L.
Sun
G.
Lawson
G.
Kato
M.
Natarajan
R.
Inhibiting microRNA-192 ameliorates renal fibrosis in diabetic nephropathy
J. Am. Soc. Nephrol.
2012
, vol. 
23
 (pg. 
458
-
469
)
10
Chung
A.C.
Huang
X.R.
Meng
X.
Lan
H.Y.
miR-192 mediates TGF-β/Smad3-driven renal fibrosis
J. Am. Soc. Nephrol.
2010
, vol. 
21
 (pg. 
1317
-
1325
)
11
Kalluri
R.
Weinberg
R.A.
The basics of epithelial-mesenchymal transition
J. Clin. Invest.
2009
, vol. 
119
 (pg. 
1420
-
1428
)
12
Kalluri
R.
EMT: when epithelial cells decide to become mesenchymal-like cells
J. Clin. Invest.
2009
, vol. 
119
 (pg. 
1417
-
1419
)
13
Kim
T.
Veronese
A.
Pichiorri
F.
Lee
T.J.
Jeon
Y.J.
Volinia
S.
Pineau
P.
Marchio
A.
Palatini
J.
Suh
S.S.
, et al. 
p53 regulates epithelial–mesenchymal transition through microRNAs targeting ZEB1 and ZEB2
J. Exp. Med.
2011
, vol. 
208
 (pg. 
875
-
883
)
14
Park
S.M.
Gaur
A.B.
Lengyel
E.
Peter
M.E.
The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2
Genes Dev.
2008
, vol. 
22
 (pg. 
894
-
907
)
15
Gregory
P.A.
Bert
A.G.
Paterson
E.L.
Barry
S.C.
Tsykin
A.
Farshid
G.
Vadas
M.A.
Khew-Goodall
Y.
Goodall
G.J.
The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1
Nat. Cell Biol.
2008
, vol. 
10
 (pg. 
593
-
601
)
16
Brabletz
S.
Brabletz
T.
The ZEB/miR-200 feedback loop: a motor of cellular plasticity in development and cancer?
EMBO Rep.
2010
, vol. 
11
 (pg. 
670
-
677
)
17
Carthew
R.W.
Sontheimer
E.J.
Origins and mechanisms of miRNAs and siRNAs
Cell
2009
, vol. 
136
 (pg. 
642
-
655
)
18
Cullen
B.R.
Transcription and processing of human microRNA precursors
Mol. Cell
2004
, vol. 
16
 (pg. 
861
-
865
)
19
Filipowicz
W.
Bhattacharyya
S.N.
Sonenberg
N.
Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight?
Nat. Rev. Genet.
2008
, vol. 
9
 (pg. 
102
-
114
)
20
Hino
K.
Tsuchiya
K.
Fukao
T.
Kiga
K.
Okamoto
R.
Kanai
T.
Watanabe
M.
Inducible expression of microRNA-194 is regulated by HNF-1α during intestinal epithelial cell differentiation
RNA
2008
, vol. 
14
 (pg. 
1433
-
1442
)
21
Jenkins
R.H.
Martin
J.
Phillips
A.O.
Bowen
T.
Fraser
D.J.
Transforming growth factor β1 represses proximal tubular cell microRNA-192 expression via decreased hepatocyte nuclear factor DNA binding
Biochem. J.
2012
, vol. 
443
 (pg. 
407
-
416
)
22
Xiong
M.
Jiang
L.
Zhou
Y.
Qiu
W.
Fang
L.
Tan
R.
Wen
P.
Yang
J.
The miR-200 family regulates TGF-β1-induced renal tubular epithelial to mesenchymal transition through Smad pathway by targeting ZEB1 and ZEB2 expression
Am. J. Physiol. Renal Physiol.
2012
, vol. 
302
 (pg. 
F369
-
F379
)
23
Meng
Z.
Fu
X.
Chen
X.
Zeng
S.
Tian
Y.
Jove
R.
Xu
R.
Huang
W.
miR-194 is a marker of hepatic epithelial cells and suppresses metastasis of liver cancer cells in mice
Hepatology
2010
, vol. 
52
 (pg. 
2148
-
2157
)
24
Mendell
J.T.
miRiad roles for the miR-17-92 cluster in development and disease
Cell
2008
, vol. 
133
 (pg. 
217
-
222
)
25
Olive
V.
Bennett
M.J.
Walker
J.C.
Ma
C.
Jiang
I.
Cordon-Cardo
C.
Li
Q.J.
Lowe
S.W.
Hannon
G.J.
He
L.
miR-19 is a key oncogenic component of mir-17–92
Genes Dev.
2009
, vol. 
23
 (pg. 
2839
-
2849
)
26
Igarashi
P.
Shao
X.
McNally
B.T.
Hiesberger
T.
Roles of HNF-1β in kidney development and congenital cystic diseases
Kidney Int.
2005
, vol. 
68
 (pg. 
1944
-
1947
)
27
Jiang
S.
Tanaka
T.
Iwanari
H.
Hotta
H.
Yamashita
H.
Kumakura
J.
Watanabe
Y.
Uchiyama
Y.
Aburatani
H.
Hamakubo
T.
, et al. 
Expression and localization of P1 promoter-driven hepatocyte nuclear factor-4α (HNF4α) isoforms in human and rats
Nucl. Recept.
2003
, vol. 
1
 pg. 
5
 
28
Bingham
C.
Hattersley
A.T.
Renal cysts and diabetes syndrome resulting from mutations in hepatocyte nuclear factor-1β
Nephrol., Dial., Transplant.
2004
, vol. 
19
 (pg. 
2703
-
2708
)
29
Pichiorri
F.
Suh
S.S.
Rocci
A.
De Luca
L.
Taccioli
C.
Santhanam
R.
Zhou
W.
Benson
D.M.
Jr
Hofmainster
C.
Alder
H.
, et al. 
Downregulation of p53-inducible microRNAs 192, 194, and 215 impairs the p53/MDM2 autoregulatory loop in multiple myeloma development
Cancer Cell
2010
, vol. 
18
 (pg. 
367
-
381
)
30
Georges
S.A.
Biery
M.C.
Kim
S.Y.
Schelter
J.M.
Guo
J.
Chang
A.N.
Jackson
A.L.
Carleton
M.O.
Linsley
P.S.
Cleary
M.A.
Chau
B.N.
Coordinated regulation of cell cycle transcripts by p53-inducible microRNAs, miR-192 and miR-215
Cancer Res.
2008
, vol. 
68
 (pg. 
10105
-
10112
)
31
Boni
V.
Bitarte
N.
Cristobal
I.
Zarate
R.
Rodriguez
J.
Maiello
E.
Garcia-Foncillas
J.
Bandres
E.
miR-192/miR-215 influence 5-fluorouracil resistance through cell cycle-mediated mechanisms complementary to its post-transcriptional thymidilate synthase regulation
Mol. Cancer Ther.
2010
, vol. 
9
 (pg. 
2265
-
2275
)
32
Braun
C.J.
Zhang
X.
Savelyeva
I.
Wolff
S.
Moll
U.M.
Schepeler
T.
Orntoft
T.F.
Andersen
C.L.
Dobbelstein
M.
p53-responsive microRNAs 192 and 215 are capable of inducing cell cycle arrest
Cancer Res.
2008
, vol. 
68
 (pg. 
10094
-
10104
)
33
Feng
S.
Cong
S.
Zhang
X.
Bao
X.
Wang
W.
Li
H.
Wang
Z.
Wang
G.
Xu
J.
Du
B.
, et al. 
MicroRNA-192 targeting retinoblastoma 1 inhibits cell proliferation and induces cell apoptosis in lung cancer cells
Nucleic Acids Res.
2011
, vol. 
39
 (pg. 
6669
-
6678
)
34
Song
B.
Wang
Y.
Kudo
K.
Gavin
E.J.
Xi
Y.
Ju
J.
miR-192 regulates dihydrofolate reductase and cellular proliferation through the p53-microRNA circuit
Clin. Cancer Res.
2008
, vol. 
14
 (pg. 
8080
-
8086
)
35
El-Dahr
S.S.
Aboudehen
K.
Saifudeen
Z.
Transcriptional control of terminal nephron differentiation
Am. J. Physiol. Renal Physiol.
2008
, vol. 
294
 (pg. 
F1273
-
F1278
)
36
Xu
H.
He
J.H.
Xiao
Z.D.
Zhang
Q.Q.
Chen
Y.Q.
Zhou
H.
Qu
L.H.
Liver-enriched transcription factors regulate microRNA-122 that targets CUTL1 during liver development
Hepatology
2010
, vol. 
52
 (pg. 
1431
-
1442
)
37
Zeng
X.
Lin
Y.
Yin
C.
Zhang
X.
Ning
B.F.
Zhang
Q.
Zhang
J.P.
Qiu
L.
Qin
X.R.
Chen
Y.X.
Xie
W.F.
Recombinant adenovirus carrying the hepatocyte nuclear factor-1α gene inhibits hepatocellular carcinoma xenograft growth in mice
Hepatology
2011
, vol. 
54
 (pg. 
2036
-
2047
)
38
Godwin
J.G.
Ge
X.
Stephan
K.
Jurisch
A.
Tullius
S.G.
Iacomini
J.
Identification of a microRNA signature of renal ischemia reperfusion injury
Proc. Natl. Acad. Sci. U.S.A.
2010
, vol. 
107
 (pg. 
14339
-
14344
)
39
Wang
G.
Tam
L.S.
Li
E.K.
Kwan
B.C.
Chow
K.M.
Luk
C.C.
Li
P.K.
Szeto
C.C.
Serum and urinary free microRNA level in patients with systemic lupus erythematosus
Lupus
2011
, vol. 
20
 (pg. 
493
-
500
)
40
Zarjou
A.
Yang
S.
Abraham
E.
Agarwal
A.
Liu
G.
Identification of a microRNA signature in renal fibrosis: role of miR-21
Am. J. Physiol. Renal Physiol.
2011
, vol. 
301
 (pg. 
F793
-
F801
)
41
Long
J.
Wang
Y.
Wang
W.
Chang
B.H.
Danesh
F.R.
MicroRNA-29c is a signature microRNA under high glucose conditions that targets Sprouty homolog 1, and its in vivo knockdown prevents progression of diabetic nephropathy
J. Biol. Chem.
2011
, vol. 
286
 (pg. 
11837
-
11848
)
42
Wang
G.
Kwan
B.C.
Lai
F.M.
Choi
P.C.
Chow
K.M.
Li
P.K.
Szeto
C.C.
Intrarenal expression of microRNAs in patients with IgA nephropathy
Lab. Invest.
2010
, vol. 
90
 (pg. 
98
-
103
)
43
Wang
G.
Kwan
B.C.
Lai
F.M.
Choi
P.C.
Chow
K.M.
Li
P.K.
Szeto
C.C.
Intrarenal expression of miRNAs in patients with hypertensive nephrosclerosis
Am. J. Hypertens.
2010
, vol. 
23
 (pg. 
78
-
84
)
44
Wang
X.X.
Jiang
T.
Shen
Y.
Caldas
Y.
Miyazaki-Anzai
S.
Santamaria
H.
Urbanek
C.
Solis
N.
Scherzer
P.
Lewis
L.
, et al. 
Diabetic nephropathy is accelerated by farnesoid X receptor deficiency and inhibited by farnesoid X receptor activation in a type 1 diabetes model
Diabetes
2010
, vol. 
59
 (pg. 
2916
-
2927
)
45
Mizutani
A.
Koinuma
D.
Tsutsumi
S.
Kamimura
N.
Morikawa
M.
Suzuki
H.I.
Imamura
T.
Miyazono
K.
Aburatani
H.
Cell type-specific target selection by combinatorial binding of Smad2/3 proteins and hepatocyte nuclear factor 4α in HepG2 cells
J. Biol. Chem.
2011
, vol. 
286
 (pg. 
29848
-
29860
)
46
Minoo
P.
Hu
L.
Zhu
N.
Borok
Z.
Bellusci
S.
Groffen
J.
Kardassis
D.
Li
C.
SMAD3 prevents binding of NKX2.1 and FOXA1 to the SpB promoter through its MH1 and MH2 domains
Nucleic Acids Res.
2008
, vol. 
36
 (pg. 
179
-
188
)
47
Nagel
R.
Clijsters
L.
Agami
R.
The miRNA-192/194 cluster regulates the Period gene family and the circadian clock
FEBS J.
2009
, vol. 
276
 (pg. 
5447
-
5455
)
48
Elvira-Matelot
E.
Zhou
X.O.
Farman
N.
Beaurain
G.
Henrion-Caude
A.
Hadchouel
J.
Jeunemaitre
X.
Regulation of WNK1 expression by miR-192 and aldosterone
J. Am. Soc. Nephrol.
2010
, vol. 
21
 (pg. 
1724
-
1731
)