Abstract

The classification of diabetic nephropathy (DN) as a vascular complication of diabetes makes the possible involvement of histamine, an endogenous amine that is well known for its vasoactive properties, an interesting topic for study. The aim of the present review is to provide an extensive overview of the possible involvement of histamine in the onset and progression of DN. The evidence collected on the role of histamine in kidney function together with its well-known pleiotropic action suggest that this amine may act simultaneously on glomerular hyperfiltration, tubular inflammation, fibrosis development and tubular hypertrophy.

Diabetic nephropathy (DN) affects approximately one-third of diabetes mellitus patients and is associated with a substantially elevated mortality rate [1], which is due to an increase in all-cause mortality and a concomitant decline in renal function. The main pharmacological strategies for its treatment currently involve the blockade of the renin–angiotensin–aldosterone (RAAS) system. However, these approaches are suboptimal and their efficacy greatly depends on the early initiation of therapy. The search for new therapeutic strategies is therefore highly warranted, but still a challenge that requires a better understanding of DN pathogenesis.

DN can be considered the result of the interactions between multiple metabolic and haemodynamic factors that activate common intracellular signalling pathways, such as protein kinase C (PKC), mitogen activated protein kinase (MAPK), and nuclear factor-κB (NF-κB), which, in turn, trigger the production of cytokines and growth factors, leading to renal disease [2]. The RAAS system, endothelin and urotensin II are vasoactive hormones that have been extensively studied. Other mediators may be involved, although their relation to DN is still speculative. In particular, histamine, in keeping with its well-known vascular and pro-inflammatory effects, is an interesting target for exploration. Indeed, DN is considered a microvascular compliance of diabetes which establishes a vicious circle between glomerular hyperfiltration, tubular inflammation, hypertrophy and interstitial fibrosis development, with synergistic effects. The identification of mediators that can simultaneously affect these multiple events would translate into new pharmacological targets. Histamine was initially related to the vascular genesis of glomerular hyperfiltration. However, a more complex role for histamine can be hypothesised since the tubular hypothesis of DN pathogenesis was postulated. This review aims to elucidate histamine’s contribution to the vicious circle of DN.

Histamine source in diabetic kidneys

Markle et al. (1986) [3] were the first to demonstrate that diabetic rats show an increase in whole kidney histamine content, of up to 45%. Notably, they also used a pharmacological approach to provide the first evidence that this increase was due to the neo-synthesis of histamine from its precursor l-histidine by the histidine decarboxylase (HDC) enzyme. Indeed, the administration of the selective HDC inhibitor α-hydrazinohistidine (25 mg/kg/day ip for 2 weeks) inhibited this increase almost to control levels. These data are consistent with the increased systemic level of histamine reported in diabetic patients with peripheral vascular disease [4], suggesting that histamine may play a functional role in the development of diabetes and its microvascular complications. This hypothesis has been supported by the more recent observation that the deletion of the HDC enzyme, which synthesises histamine from its precursor l-histidine and can therefore be considered a marker for histamine biosynthesis [5], prevents the development of autoimmune diabetes in NOD mice [6]. However, these data draw attention to the question of whether the source of histamine in diabetic kidneys is systemic circulation or a local inducible histamine pool. The first hypothesis has actually been discarded after the observation of the presence of the HDC enzyme in the kidney specimens of both humans and mice. Indeed, the histamine concentration in the glomeruli was found to be much higher than the circulating concentration (10−6 compared with 10−8 M respectively) [7]. In particular, it was demonstrated, using an enzymatic assay on tissue homogenates, that diabetic rats show significantly higher HDC renal activity (+79%) and no decreases in the activity of histaminase, which is one of the enzymes that catalyses histamine decomposition in tissues [8]. Consequently, an increase of up to 81% in histamine content in the kidneys of diabetic rats, as compared with controls, has also been demonstrated [9]. Attempts to identify mast cells (MC) in the kidneys were pursued for a long time as MCs are the main source of histamine in tissue. The MC number in the kidneys is typically very low [10], in non-diabetic conditions, unlike in other anatomical districts where MC can be constitutively found. However, their presence increases in a variety of human diseases [10], including DN. Increased numbers of MC that express type VIII collagen [11], as well as MC chymase and tryptase [12], have been observed in the renal biopsies of DN patients. Notably, several hyperglycaemia-related metabolic by-products (such as ROS and oxidised lipoproteins) trigger MC degranulation [13], which has been found to parallel the development of DN through the stages of the disease [12]. The role of MC in DN involves the activation of the local RAAS systems, via the release, by MC, of chymase, a chymotrypsin-like serine protease potent inducer of angiotensin II [14]. However, histamine that is released from MC may also contribute to RAAS system activation [15]. In 1982, Schwertschlag and Hackenthal [16] demonstrated that MC-derived histamine was able to stimulate the release of renin from rat kidneys by H2R activation.

Despite HDC in MC, which is usually the major source of histamine, and renal MCs are increased in DN together with the histamine levels, a non-MC HDC is considered to be the prevalent source of histamine. Indeed, three observations have to be considered: (i) renal histamine content in non-diabetic conditions, in which MC number is very low, is already higher than plasmatic content (10−6 compared with 10−8 M, respectively) [7]; (ii) compelling evidence from both enzymatic assays (on homogenates of glomeruli and tubules from the medulla and cortex) and immunohistochemical analyses (on isolated cells and kidney specimens) revealed that HDC was localised mainly in the cortex, both in the glomerulus [7,17] and tubules [18,19]; (iii) HDC expression on renal residential cells was found to be significantly up-regulated in diabetic mice [19]. Collectively, these data clearly demonstrate the existence of a local intra-renal inducible histamine pool. Interestingly, it has been shown that carnosine, which is a dietary essential amino acid whose plasmatic levels are low in chronic kidney disease patients [20], is an adjunctive reservoir for l-histidine. Carnosine, which is a dipeptide formed of β-alanine and l-histidine, has been found in several histamine-rich anatomical districts, including the kidneys, in an inverse correlation with histamine levels [21]. Interestingly, polymorphism in the the gene encoding for carnosinase-1 (CNDP1), which is a circulating enzyme that degrades the dipeptide carnosine into β-alanine and l-histidine, has been associated with the risk of nephropathy in type 2 diabetic patients. However, carnosine treatment has been found to restrain glomerular apoptosis, to prevent podocyte loss and to reduce the expression of Bcl-2-associated X protein and cytochrome c [22], by inhibiting advanced glycoxidation end-product (AGE) and advanced lipoxidation end-product (ALE) formation [23], via a histamine-independent pathway.

The detrimental effect of histamine in diabetic kidneys can be mediated by all four of its receptors (histamine receptor (HRs)). Indeed, a complementary immunohistochemical and pharmacological approach has demonstrated that they are all expressed in the kidneys: H1R had the widest distribution as it was present in the glomeruli (podocyte and mesangial cells) and both the proximal and distal tubules; H2R shared the glomeruli (mesangial cells) and distal tubule localisation with H1R; H3R seemed to be restricted to the apical side of the principal cells of the collecting duct; H4R was found at the proximal tubules and at the loop of Henlé [7,17,24–27]. Notably, the up-regulation of the histaminergic tone in the diabetic kidney is related to the overexpression of at least two of the four HRs, which is in accordance with the increased renal histamine levels; in particular, H3R [26] at the collecting duct, and H4R mainly at the proximal tubules and at the loop of Henlé [17,25]. The potential contribution of HR activation to the DN vicious circle will be explored below.

Histamine and glomerular hyperfiltration

Glomerular hyperfiltration stems from mechanical damage to the glomerulus that involves podocyte detachment and loss, extracellular matrix deposition and endothelial dysfunction. Histamine is thought to participate in at least two of these detrimental events: podocyte detachment and endothelial dysfunction. It is well accepted that glomerular hyperfiltration reflects generalised microvascular and macrovascular functional changes [28–30]. Its well-known vasoactive properties [31] led scientists to think that the nascent or inducible histamine pool observed in experimental models of diabetes triggered microvessel alterations and large vessel hyperpermeability, thus contributing to both the diabetic microangiopathy and macroangiopathy [32], that are at the base of glomerular hyperfiltration. In the aortic endothelial and subjacent smooth muscle cells of diabetic rats, HDC activity increased by 250% and over 300%, respectively, over the 4-week period after diabetes induction. Parallel histaminase activity was reduced by 50% in the aortic endothelial cells and by 30% in the subjacent smooth muscle cells and the intracellular histamine content increased to 138 and 150% respectively [33]. The neo-synthesis of histamine at the aortic level was confirmed by the inhibitory effect of α-HH, which was also able to reduce the aortic albumin flux in diabetic rats by 83% [34]. It can therefore be stated that histamine is clearly a mediator of aortic macromolecule uptake in diabetes. Nevertheless, histamine levels in coronary circulation were found to increase during myocardial ischaemia, irrespective of the incidence of risk factors, diabetes included [35].

The increased histaminergic tone on the vascular level can trigger hyperpermeability in various microcirculatory beds. For instance, diabetic rats showed an increased blood–brain barrier permeability within 2–4 weeks after the onset of hyperglycaemia, and this effect was mediated by H1R [36–39].

Yousif et al. [40] have demonstrated, in an ex-vivo perfused kidney model, that exogenous histamine-induced vasodilation in diabetic rat-derived kidneys is mediated by both endothelium-derived nitric oxide (EDNO) and the endothelium-derived hyperpolarising factor (EDHF), which open the Ca2+-activated K+ channels (SKCa). SKCa have been found to have no impact on afferent arteriolar tone in normal kidneys [41]. However, SKCa-mediated relaxation is reduced in the resistance arteries of diabetic rats [42–44]. It is worth noting that the well-known anti-diabetic drug metformin has been found to restore SKCa-mediated vasodilatation, which had been impaired by AGEs in rat mesenteric arteries [45].

The vascular events evoked by histamine translated to the renal circulatory bed could lead to an increase in renal plasma flow and pressure and an increase in glomerular filtration rate (GFR), which characterises the early phase of DN [46]. Consistently, it was found that the infusion of different H1R antagonists/inverse agonists causes a drop in the GFR induced by aortic clamping [47]. However, apart from vasodilation, different events regulate GFR in DN and with the disease progression the GFR declines in parallel with a further rise in albuminuria [48]. The reduction in filtration area, caused by fenestration and podocyte loss, is one contributor to GFR decline.

Histamine is known to act biphasically on vascular permeability: within seconds to minutes, it evokes a rapid transient increase in permeability that is caused by endothelial gaps [49–54], while within hours it causes prolonged vascular leakage by acting on the expression of the zonula occludens (ZO)-1 protein [55]. These events have been explored particularly at the ocular level in order to test the hypothesis that histamine may act as a mediator of diabetic retinopathy. Gardner (1995) [56] demonstrated that histamine contributes to the retinal blood barrier permeability breakdown in diabetic retinopathy. H1R antagonism could therefore be a therapeutic strategy for diabetic retinopathy and the hypothesis of the use of a similar strategy for DN has also appeared [57]. However, the Astemizole Retinopathy Trial, which aimed to evaluate the efficacy of the H1R antagonist in diabetic macular oedema, revealed no clinical effect [58], leading to the strategy being abandoned for the treatment of DN.

In the kidney, histamine can affect the integrity of permeability barriers. Indeed, histamine has been reported to affect zonula occludens 1 (ZO-1) and P-cadherin expression in human immortalised podocytes [17]. Both these junctional proteins play pivotal roles in maintaining the cytoarchitecture of the slit diaphragm (SD), and disturbing them may contribute to podocyte detachment and loss. Notably, only chlorpheniramine, a selective anti-H1R, was effective in preserving SD integrity, including a potential positive effect on the prevention of podocyte loss and consequently on glomerular filtration barrier integrity, while ranitidine (selective H2R antagonist) and JNJ7777120 (the H4R antagonist prototype) provided no effect [17]. Histamine may therefore exert direct effects on glomerular hyperfiltration, through H1R, in addition to its well-known vascular activities. Notably, levocetirizine (0.5 mg/kg/day orally for 8 weeks) increased creatinine and urea clearance in a model of streptozotocin-induced diabetes in rats, and almost restored the GFR, while simultaneously reducing proteinuria and polyuria [59]. Although a quantitative morphological analysis of the filtration barrier was not performed, the functional data, together with the classical histological by Periodic acid–Schiff (PAS)- and Masson’s trichrome-staining, support the existence of a beneficial effect on glomerular filtration barrier integrity. These data are in keeping with the observation by Ichikawa and Brenner [60] of a decrease in the ultrafiltration coefficient following histamine dependent-H1R activation. Consistently, in a model of anti-glomerular basement membrane induced glomerulonephritis, both the H1R antagonist diphenhydramine and the H2R antagonist cimetidine prevented the GFR decrease [61].

Glomerular hyperfiltration could be also the result of a tubular effect. The hyper-reabsorption at the proximal tubule, triggered by hyperfiltration as a compensatory mechanism, decreases electrolyte load to the macula densa, thus inhibiting the tubulo-glomerular feedback (TGF) and causing an increase in the colloid osmotic pressure of the glomerular capillaries and hyperfiltration [48]. Indeed, in a mouse model of diabetes H4R blockade by JNJ39758979 restored to control level the drop in the creatinine clearance [19], an indirect measure of GFR. These animals showed a restored level of the Na+-H+ exchange 3 (NHE)3, responsible for the Na+ load to the macula densa.

Histamine and tubular inflammation

Tubular inflammation is a hallmark of progressive renal disease [62]. DN inflammation is sterile and chronic and is triggered by intrinsic epithelium cell injury [63], which can produce a number of chemokines promoting a pro-inflammatory microenvironment amplifying renal injury [64]. These events promote the kidney infiltration of monocytes and lymphocytes, which further increases the inflammatory response, promotes cell injury and the development of fibrosis [64].

The inflammatory properties of histamine were among the first properties described for the amine [65]. Indeed, according to the triple response described by Lewis and Grant in 1924 [31], the vascular changes that occur in acute inflammation are accompanied by the recruitment of neutrophils and mononuclears, which cross the endothelial junctions and penetrate the vessel wall. Leucocytes are thereafter recruited through chemotaxis. Two of the four HRs are implicated in these events: H1R promotes cellular migration [66], while H4R activation mediates eosinophil adhesion to the endothelium and chemotaxis [67], up-regulating the cell surface proteins CD11b/CD18 (Mac-1) and CD54 (ICAM-1) on human eosinophils [68]. Following H4R activation, the rearrangement of the actin cytoskeleton of eosinophils facilitates cell migration into the inflammation sites [69]. Notably, Dai et al. [70] have demonstrated that interstitial eosinophil aggregation is more common in the renal biopsies of DN patients than in other types of glomerulopathy, such as IgA nephropathy, membranous nephropathy and membranoproliferative glomerulonephritis. Moreover, the severity of interstitial fibrosis and tubular atrophy was the only predictor factor for interstitial eosinophil aggregation in DN. It is reasonable to conclude that eosinophil aggregation is a consequence of inflammatory response and that it perpetuates tubulointerstitial injury. Notably, the preventive chronic administration of the H4R antagonist JNJ39758979 (Ki = 12.5 ± 2.6 nM) led to a significant reduction in the number of leucocytes, compared with untreated diabetic animals, 15 weeks after diabetes onset in a model of streptozotocin-induced DN in DBA2/J mice [19].

The chemotactic effects of histamine not only involve eosinophils, but also neutrophils: they evoke lysosomal enzyme release [71], and thus enhance the inflammatory response to direct tissue damage. Histamine is also involved in T-cell proliferation and lymphokine release, the induction of cytotoxic T cells and the promotion of their cytolytic activity, as well as B-cell differentiation into effector cells [72]. All these infiltrating cells contribute, together with macrophages, dendritic cells and renal tubular cells to inflammation in DN [63].

Beyond inflammatory cell recruitment, histamine is also known to exert other inflammatory properties in several cellular systems. For instance, histamine activates the NF-κB pathway by inducing the expression of NF-κB p65 and p-IκBα in human nasal epithelial cells (HNEpCs) [73]. The H1R antagonist cetirizine has been demonstrated to not only inhibit the recruitment and activation of inflammatory cells, but to also suppress the production of reactive oxygen radicals and lipid mediators [74–77]. It is therefore possible to speculate that similar effects are evoked by histamine in renal cells.

More interestingly, histamine, acting both as a paracrine and autocrine stimulus, has been observed to increase the mRNA levels of interleukin (IL)-6 [73], a cytokine involved in several renal diseases including DN [78,79]. In particular, IL-6 overexpression in diabetic kidneys has been correlated with kidney hypertrophy, albumin excretion, mesangial expansion and glomerular basement membrane thickening [64].

Another factor that has been extensively linked to DN is IL-18 [80], by which serum and urinary levels have been previously correlated with albuminuria. The major source of this pro-inflammatory cytokine is the tubular epithelial cells, but it is also produced by infiltrating monocyte-macrophages and T cells [64]. The induction of IL-18 secretion from peripheral blood mononuclear cells (PBMCs) [81] may be an additional contribution to the inflammatory milieu of DN by histamine. However, a more recent study has demonstrated the existence of functional antagonism between IL-18 and histamine, which occurs via H2R stimulation, in monocyte ICAM-1 expression [82].

On the other hand, the effect of histamine on tumour necrosis factor (TNF)-α (TNF-α), another relevant pro-inflammatory cytokine that is associated/involved with DN and interstitial tubular nephritis [83], is contradictory. TNF-α has been implicated in haemodynamic changes, affecting the GFR and the endothelial permeability, and its urinary excretion has been correlated with DN progression [64]. TNF-α is produced not only by monocytes, macrophages and T cells, but also by all the resident renal cells [64]. Moreover, TNF-α is stored and released by MC and can be released [84] together with histamine, which in turn can stimulate the release of TNF-α in an autocrine manner [85]. However, histamine has been reported to antagonise TNF-α by shedding its receptor, TNFR1, via H1R activation in human umbilical vein endothelial cells (HUVECs) [86] and to suppress TNF-α synthesis via H2R in PBMC and monocytes [87].

Finally, histamine is also able to activate the Tissue Factor (TF) pathway. It has been reported that endothelial TF expression and activity is induced by histamine [88], via H1R activation [89] and is induced in vascular inflammation. TF is involved in DN development [80] and is increased with DN severity [90].

Histamine and tubular fibrosis

The inflammatory properties of histamine and its role in promoting and sustaining inflammatory cell infiltration are linked to fibrosis development, which suggests that histamine may be a target for the management of kidney fibrosis. Glomerular and tubulointerstitial infiltration by inflammatory cells, including neutrophils, macrophages and lymphocytes, which release pro-fibrotic cytokines [91], occur from the early stage of DN. Such cellular infiltrates have been reported in both animal experimental models and human renal biopsies [92]. Of the various inflammatory cells involved, a prominent role can be attributed to macrophages, whose accumulation has been related to the severity of DN [93].

The differentiation of monocytes into macrophages has been associated with an imbalance in the native HRs on these cells. H1R is up-regulated during differentiation, thus increasing the histaminergic response, while H2R is down-regulated [94]. The role of histamine in macrophage activation is further confirmed by in vitro data. H4R induces chemotaxis and phagocytosis in both human (RAW 264.7 cell line) and murine (bone marrow-derived macrophages (BMM)) monocytes [95]. Finally, macrophages and lymphocytes have also been found to be an alternative source of histamine, with a content of approximately 0.05 pg histamine/cell, in a histamine-specific RIA. Both the ionophore A23187 and the complement component 5a caused histamine release, of up to 50 and 40%, respectively, from monocytes [96].

Once again histamine is seen to induce and perpetuate the pathological events that underlie renal failure in DN, exerting both autocrine and paracrine effects on a range of inflammatory cells.

Macrophages are also a major source of transforming growth factor-β1 (TGF-β1), which is the master regulator of fibrosis and a potent chemoattractant for macrophages/monocytes. In DN, TGF-β1 can be considered one of the principal mediators of parenchymal/stromal alterations, which finally lead to tissue architecture disruption [97]. TGF-β1 up-regulation causes the imbalance in extracellular matrix turnover, promoting the excessive deposition of collagen fibres and inhibiting their degradation at the same time. TGF-β1 also causes the transdifferentiation of parenchymal into stromal cells. For example, it brings about the transformation of tubule epithelial cells into myofibroblasts [98,99]. This process is responsible for interstitial renal fibrosis. TGF-β1 overexpression, together with the consequent extracellular matrix accumulation and parenchymal cell transdifferentiation, is closely associated with renal failure [100]. TGF-β1 is therefore an attractive target when attempting to counteract fibrotic processes. The only current strategy that directly targets TGF-β1 is based on the use of monoclonal antibodies, such as fresolimumab, for the treatment of pulmonary fibrosis [101]. It has been tested in a phase I study for primary focal segmental glomerulosclerosis [102]. However, recent data suggest that antihistamine anti-H4R compounds can be used to regulate TGF-β1 release and effects. Indeed, in vivo studies carried out on a model of bleomycin-induced lung fibrosis clearly demonstrate that H4R antagonism counteracts fibrosis establishment by acting on TGF-β production [103,104]. TGF-β, in turn, modulates the fibrotic process by impacting upon downstream signalling. Notably, the down-regulation of TGF-β by JNJ7777120 (the H4R antagonist prototype) has been sustained by a reduction in Smad 3 phosphorylation and, consequently, Smad3/Smad4 complex formation [103]. The Smad family is one of the most commonly studied pathways and is closely involved with TGF-β1. Focusing on the renal fibrotic process, the presence of Smad 3 and Smad 4 has been evaluated as being pathogenic while that of Smad 2 and Smad 7 has been related to renoprotective effects [105–108]. The decreased level of Smad 7 expression causes persistent inflammation and, as a result, leads to renal fibrosis via TGF-β and Smad 3. It is therefore plausible that the anti-fibrotic effect exerted by JNJ39758979 in a model of murine DN [19] is related, at least partially, to the modulation of TGF-β/Smad signalling in the kidneys.

Nevertheless, H1R can also modulate the fibrotic response. Indeed, levocetirizine-treated diabetic rats have shown a reduction in renal TGF-β1 [59]. Whether this is a direct consequence of H1R antagonism, or rather an indirect event is still to be established. However, the anti-inflammatory effect, evaluated in terms of the restoration of TNF-α levels and nitric oxide (NO) bioavailability [59], may be a possible mechanistic interpretation of the anti-fibrotic result. Moreover, on kidney fibroblasts the presence of the H1R, whose activation promotes cell proliferation, TGF-β synthesis and collagen production [109], may further support the involvement of this receptor in fibrosis development.

Actually, no other study apart the one from Pini et al. [19] and Anbar et al. [59] evaluated the effect of histamine blockade on renal fibrosis during DN, therefore just speculation are possible so far. However, the measurements of TGF-β1 renal level in diabetic rats treated with levocetirizine [59] and the evaluation by Picrosirius Red staining of collagen fibre deposition after JNJ39758979 treatment of diabetic mice [19] support the hypothesis that at least H1R and H4R are both involved, directly or indirectly (through the reduction in pro-inflammatory infiltrating cells), in renal fibrosis development.

Histamine and tubular reabsorption

Recently, proximal tubule as initiator, driver or contributor in the pathogenesis of DN becomes an intriguing hypothesis. Impaired tubular uptake and increased glomerular leakage are both potentially responsible for microalbuminuria early stage of DN [110]. Indeed, the TGF presence can explain a reduction in GFR during inhibition of proximal tubular reabsorption: the increased electrolyte load to the macula densa due to a reduction in reabsorption led to afferent arteriolar vasoconstriction and consequently to a GFR correction [111]. Sodium and chloride appear to be the preferential electrolyte regulating the TGF. This tubulo-centric hypothesis could be considered the basis for the development of the newest anti-diabetic class, the sodium glucose co-transporter (SGLT)-2 inhibitors. Interestingly, their nephro-protective effects can be due to a functional link between SGLT2 and the NHE3, an important determinant of Na+ tubular reabsorption. When SGLT2 is inhibited, NHE3 is inhibited too [110].

Tubular reabsoprtion impairment could also contribute to albuminuria onset in DN [112]. Despite the canonical idea of an increase in creatinine and urinary albumin excretion due to glomerular hypertension and hyperfiltration in the early phase of DN [46], more recent evidence are in favour of an unchanged glomerular albumin filtration, but a decrease in tubular albumin reabsorption [113,114]. Major contributor to albumin dynamics associated with the hyperfiltration status of DN is the megalin/cubilin complex [115]. Interestingly, in two models of insulin-deficient diabetes in drug-inducible megalin knockout mice, both albumin filtration and reabsorption were increased [116].

Overall these evidence highlights the importance of tubular reabsorptive processes in DN onset and progression.

The role of histamine in tubular reabsorption has been less investigated than the other fields. Therefore, only speculation can be made, and most of them are based on a parallelism with other epithelial tissues. The only reabsorption mechanisms that have seen some partial investigation are the megalin and NHE3 pathways in the proximal tubule. Hyperglycaemia is known to induce a reduction in megalin expression and a parallel increase in NHE3 expression and activity [117]. JNJ39758979 treatment preserved the expression and apical membrane localisation of megalin as well as the expression level of NHE3 in a mouse model of DN. These events were paralleled by a restoration of the albumin-to-creatinine ratio and creatinine clearance and by preserved glomerular integrity [19]. In accordance with the tubular hypothesis of DN [118], it is therefore possible to speculate that JNJ39758979’s beneficial effect on renal function is a consequence of its beneficial effect on the tubular reabsorption machinery. However, the question of whether this is a direct H4R-blockade effect is still far from being answered. Indeed, we can only speculate whether histamine has a direct detrimental effect on the megalin and NHE3 pathways in terms of parallelism between the angiotensin AT-1 receptor and H4R, which are both Gi-coupled receptors. Similar to JNJ39758979, losartan has also been reported to reduce NHE3 expression [119]. However, the possibility of it being an indirect effect exerted by JNJ39758979 and secondary to RAAS modulation could not be ruled out. Moreover, even if JNJ39758979 is a selective H4R antagonist, a class-effect has to be demonstrated to affirm whether H4R-dependent downstream signals are responsible for the detrimental effect of histamine on the tubular reabsortive machinery. If we consider the other reabsorption pathways in the tubules, the correlation with histamine becomes even more speculative. An explicative example can be found in the potential contribution of histamine to water-balance in the kidneys, which is usually dysregulated in DN, leading to the onset of polyuria. Several water channels, named aquaporins (AQPs), are involved in water transport across the epithelia. At least nine types, including AQP-1–8 and AQP-11 that are present at distinct sites and have specific functions, have been identified in the kidneys [120]. In particular, AQP-2 and AQP-5 urinary excretion has been observed to increase significantly in DN patients and a positive correlation between AQP level in urine and the histological class of DN has been established. Indeed, AQP-2 and AQP-5 were appointed as novel non-invasive biomarkers to help in classifying the clinical stage of DN [120]. Interestingly, an in vitro study on human nasal epithelial cells has revealed that histamine down-regulates AQP5 expression via NF-κB activation and the consequent reduction in the phosphorylation of cAMP response element-binding protein (CREB) [121,122]. These effects were mediated by H1R, as demonstrated by the ability of chlorpheniramine to reverse histamine’s inhibitory effect [122]. Moreover, H1R activation induced AQP-5 translocation to the plasma membrane in human submandibular gland cells, which, at least partly, explains the xerostomia that is induced by the classic antihistaminic anti-H1R drugs [123]. Histamine has also been found to induce gastric AQP-4 rearrangement and down-regulation [124]. It is therefore possible that histamine may also modulate AQP expression, via H1R and/or other HRs, in other epithelial cells, such as renal epithelial cells, according to their differential distribution. A deeper investigation of this issue would contribute to better understanding the mechanism that underlies the anti-polyuric effect that is exerted by both levocetirizine [59], and JNJ39758979 [19].

Conclusion

Spare evidence has been provided as to histamine’s possible role in DN in past decades [125]. Although its vasoactive and inflammatory properties may make histamine’s role in the early phase of DN progression plausible (Figure 1), this idea has not been thoroughly investigated.

Histamine’s role in the development and progression of DN

Figure 1
Histamine’s role in the development and progression of DN

Schematic representation of the hypothetical contribution of histamine in the early phases of DN development and progression. The progression of DN is the result of multiple events starting with haemodynamic and metabolic impairment and culminating in tissue remodeling. Histamine can contribute to the haemodynamic impairment. The DN progression involves endothelial cells, mesangial cells, podocytes and tubular cells. In the early phase, the TGF is disrupt: the loss of glycocalyx and the loss of fenestration between endothelial cells are the driving events of early proteinuria; the consequent glomerular hyperfiltration induces the tubular hyper-reabsorption, which in turn decreases electrolyte load to the macula densa. Histamine may affect both the glomerular hyperfiltration and the tubular hyper-reabsorption with a detrimental effect on the TGF. These events lead to tubular hypertrophy and, eventually, to glomerulosclerosis and tubule atrophy. Also matrix expansion participates to glomerulosclerosis. The establishment of a sterile inflammation further promotes the development of tubulointerstitial fibrosis. The amine is known to exert pro-inflammatory and pro-fibrotic effects.

Figure 1
Histamine’s role in the development and progression of DN

Schematic representation of the hypothetical contribution of histamine in the early phases of DN development and progression. The progression of DN is the result of multiple events starting with haemodynamic and metabolic impairment and culminating in tissue remodeling. Histamine can contribute to the haemodynamic impairment. The DN progression involves endothelial cells, mesangial cells, podocytes and tubular cells. In the early phase, the TGF is disrupt: the loss of glycocalyx and the loss of fenestration between endothelial cells are the driving events of early proteinuria; the consequent glomerular hyperfiltration induces the tubular hyper-reabsorption, which in turn decreases electrolyte load to the macula densa. Histamine may affect both the glomerular hyperfiltration and the tubular hyper-reabsorption with a detrimental effect on the TGF. These events lead to tubular hypertrophy and, eventually, to glomerulosclerosis and tubule atrophy. Also matrix expansion participates to glomerulosclerosis. The establishment of a sterile inflammation further promotes the development of tubulointerstitial fibrosis. The amine is known to exert pro-inflammatory and pro-fibrotic effects.

Initial data did not clearly establish the direct contribution of histamine to renal pathophysiology, meaning that this amine has been relegated to the background of diabetic disease and its role in DN development has not been recognised. Only two studies have investigated the effect of an antihistaminergic approach to DN, both in recent years. These studies suggest that histamine is involved in renal injury and both the selective histamine antagonism, at H1R by levocetirizine [59], and at H4R by JNJ39758979 [19], were able to prevent/reduce renal damage. However, defining whether these beneficial effects are due to the selective contribution of the HRs in the kidney is still quite the challenge. While improved glycaemic status in diabetic rats was reported with levocetirizine [59], the same positive effect was not observed with JNJ39758979 [19]. It can therefore be stated that at least H4R seems to have a selective role in renal function. However, H1R has been demonstrated to also have specific effects on podocyte junctional integrity, at least in vitro, which may contribute to renal protection. Nevertheless, the fact that indirect effects are induced by limiting the anti-inflammatory response can be recognised for both H1R and H4R antagonism. This evidence supports the idea that histamine, due to its pleiotropic actions, may simultaneously and differentially act on all the components of the vicious circle: glomerular hyperfiltration, tubular inflammation, tubular hypertrophy and fibrosis establishment. Indeed, as shown in Figure 1 histamine may exert its effects mostly on the early events of DN, contributing to the haemodynamic impairment. Moreover, it could affect the glomerular hyperfiltration and the tubular hyper-reabsorption with a detrimental effect on the TGF. Finally, the amine could exert pro-inflammatory and pro-fibrotic effects. In particular, as described in Figure 2, H1R antagonism potentially maintains glomerular integrity [17,59], while H4R antagonism protects against reabsorptive dysfunction, counteracting the imbalance of megalin/NHE3 expression at the proximal tubule [19]. Both strategies are simultaneously effective in preventing the pro-inflammatory and pro-fibrotic cascade, which leads to the loss of kidney function [19,59]. The roles of H2R and H3R are still far from being clear. However, their localisation along the nephron means that they may subserve water homoeostasis, while H2R probably contributes to glomerular mechanical damage.

HRs in the pathophysiology of DN

Figure 2
HRs in the pathophysiology of DN

DN is accompanied by an increase in renal histamine content, which can trigger and/or sustain the vicious circle established by glomerular mechanical damage, tubular inflammation, fibrosis development and tubular reabsorptive dysfunction. The strongest evidence has been found for H4R, which is localised on the proximal tubule (a) and on the loop of Henlé (b), and is involved in tubular inflammation, fibrosis and reabsorptive dysfunction. Besides promoting tubular inflammation, H1R may be involved in glomerular injury, which is consistent with its localisation in the glomerulus, but also in the tubule in both the proximal (a) and distal (c) tract. A similar effect for H2R, which is again present in the glomerulus and distal tubule (c), can be just hypothesised. A possible role for H3R in reabsorptive dysfunction can be hypothesised on the basis of its localisation in the collecting duct (d).

Figure 2
HRs in the pathophysiology of DN

DN is accompanied by an increase in renal histamine content, which can trigger and/or sustain the vicious circle established by glomerular mechanical damage, tubular inflammation, fibrosis development and tubular reabsorptive dysfunction. The strongest evidence has been found for H4R, which is localised on the proximal tubule (a) and on the loop of Henlé (b), and is involved in tubular inflammation, fibrosis and reabsorptive dysfunction. Besides promoting tubular inflammation, H1R may be involved in glomerular injury, which is consistent with its localisation in the glomerulus, but also in the tubule in both the proximal (a) and distal (c) tract. A similar effect for H2R, which is again present in the glomerulus and distal tubule (c), can be just hypothesised. A possible role for H3R in reabsorptive dysfunction can be hypothesised on the basis of its localisation in the collecting duct (d).

Targeting histamine might therefore be a novel strategy for the treatment of DN with an integrated approach of vasculoprotection, chronic inflammation reduction and fibrosis prevention. However, these suggestions merit better elucidation, including first clinical evaluations, before final conclusions can be reached.

Clinical perspectives

  • Histamine is a vasoactive amine involved in inflammatory response and fibrosis processes in the kidneys.

  • DN can be considered a vicious self-potentiating circle between glomerular hyperfiltration, tubular inflammation, fibrosis development and tubular hypertrophy.

  • Histamine targeting may be suitable as an adjuvant treatment for DN furnishing an integrated vasculoprotection, chronic inflammation reduction and fibrosis prevention approach.

Competing interests

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

Funding

This work was supported by the University of Turin (2017); and the University of Florence (2017).

Author contribution

A.C.R. and A.P. conceived and designed the study. A.C.R., A.P., and R.V. drafted the article. A.C.R. and C.G. critically revised the article for important intellectual content. R.V. and M.G. performed literature searches.

Abbreviations

     
  • AGE

    glycoxidation end-product

  •  
  • DN

    diabetic nephropathy

  •  
  • GFR

    glomerular filtration rate

  •  
  • HDC

    histidine decarboxylase

  •  
  • HR

    histamine receptor

  •  
  • HUVEC

    human umbilical vein endothelial cell

  •  
  • IL

    interleukin

  •  
  • MC

    mast cell

  •  
  • NF-κB

    nuclear factor-κB

  •  
  • NHE3

    Na+-H+ exchange 3

  •  
  • PBMC

    peripheral blood mononuclear cell

  •  
  • RAAS

    renin–angiotensin–aldosterone

  •  
  • SD

    slit diaphragm

  •  
  • SGLT

    sodium glucose co-transporter

  •  
  • SKCa

    Ca2+-activated K+ channel

  •  
  • TF

    tissue factor

  •  
  • TGF

    tubulo-glomerular feedback

  •  
  • TGF-β1

    transforming growth factor-β1

  •  
  • TNF-α

    tumour necrosis factor

  •  
  • ZO-1

    zonula occludens 1

References

References
1.
Persson
F.
and
Rossing
P.
(
2018
)
Diagnosis of diabetic kidney disease: state of the art and future perspective
.
Kidney Int. Suppl.
8
,
2
7
2.
Maric
C.
(
2008
)
Vasoactive hormones and the diabetic kidney
.
Sci. World J.
8
,
470
485
3.
Markle
R.A.
,
Hollis
T.M.
and
Cosgarea
A.J.
(
1986
)
Renal histamine increases in the streptozotocin-diabetic rat
.
Exp. Mol. Pathol.
44
,
21
28
[PubMed]
4.
Gill
D.S.
,
Barradas
M.A.
,
Fonseca
V.A.
and
Dandona
P.
(
1989
)
Plasma histamine concentrations are elevated in patients with diabetes mellitus and peripheral vascular disease
.
Metabolism
38
,
243
247
[PubMed]
5.
Watanabe
T.
and
Ohtsu
H.
(
2002
)
L-histidine decarboxylase as a probe in studies on histamine
.
Chem. Rec.
2
,
369
376
[PubMed]
6.
Alkan
M.
,
Machavoine
F.
,
Rignault
R.
,
Dam
J.
,
Dy
M.
and
Thieblemont
N.
(
2015
)
Histidine decarboxylase deficiency prevents autoimmune diabetes in NOD mice
.
J. Diabetes Res.
2015
,
965056
[PubMed]
7.
Sedor
J.R.
and
Abboud
H.E.
(
1984
)
Actions and metabolism of histamine in glomeruli and tubules of the human kidney
.
Kidney Int.
26
,
144
152
[PubMed]
8.
Gill
D.S.
,
Thompson
C.S.
and
Dandona
P.
(
1990
)
Histamine synthesis and catabolism in various tissues in diabetic rats
.
Metabolism
39
,
815
818
[PubMed]
9.
Gill
D.S.
,
Thompson
C.S.
and
Dandona
P.
(
1988
)
Increased histamine in plasma and tissues in diabetic rats
.
Diabetes Res.
7
,
31
34
[PubMed]
10.
Li
Y.
,
Liu
F.Y.
,
Peng
Y.M.
,
Li
J.
and
Chen
J.
(
2007
)
Mast cell, a promising therapeutic target in tubulointerstitial fibrosis
.
Med. Hypothes.
69
,
99
103
[PubMed]
11.
Ruger
B.M.
,
Hasan
Q.
,
Greenhill
N.S.
,
Davis
P.F.
,
Dunbar
P.R.
and
Neale
T.J.
(
1996
)
Mast cells and type VIII collagen in human diabetic nephropathy
.
Diabetologia
39
,
1215
1222
[PubMed]
12.
Zheng
J.M.
,
Yao
G.H.
,
Cheng
Z.
,
Wang
R.
and
Liu
Z.H.
(
2012
)
Pathogenic role of mast cells in the development of diabetic nephropathy: a study of patients at different stages of the disease
.
Diabetologia
55
,
801
811
[PubMed]
13.
Huang
Z.G.
,
Jin
Q.
,
Fan
M.
,
Cong
X.L.
,
Han
S.F.
,
Gao
H.
et al. .
(
2013
)
Myocardial remodeling in diabetic cardiomyopathy associated with cardiac mast cell activation
.
PLoS ONE
8
,
e60827
[PubMed]
14.
Holdsworth
S.R.
and
Summers
S.A.
(
2008
)
Role of mast cells in progressive renal diseases
.
J. Am. Soc. Nephrol.
19
,
2254
2261
15.
Balakumar
P.
,
Reddy
J.
and
Singh
M.
(
2009
)
Do resident renal mast cells play a role in the pathogenesis of diabetic nephropathy?
Mol. Cell. Biochem.
330
,
187
192
[PubMed]
16.
Schwertschlag
U.
and
Hackenthal
E.
(
1982
)
Histamine stimulates renin release from the isolated perfused rat kidney
.
Naunyn Schmiedebergs Arch. Pharmacol.
319
,
239
242
17.
Veglia
E.
,
Pini
A.
,
Moggio
A.
,
Grange
C.
,
Premoselli
F.
,
Miglio
G.
et al. .
(
2016
)
Histamine type 1-receptor activation by low dose of histamine undermines human glomerular slit diaphragm integrity
.
Pharmacol. Res.
114
,
27
38
[PubMed]
18.
Morgan
T.K.
,
Montgomery
K.
,
Mason
V.
,
West
R.B.
,
Wang
L.
,
van de Rijn
M.
et al. .
(
2006
)
Upregulation of histidine decarboxylase expression in superficial cortical nephrons during pregnancy in mice and women
.
Kidney Int.
70
,
306
314
[PubMed]
19.
Pini
A.
,
Grange
C.
,
Veglia
E.
,
Argenziano
M.
,
Cavalli
R.
,
Guasti
D.
et al. .
(
2018
)
Histamine H4 receptor antagonism prevents the progression of diabetic nephropathy in male DBA2/J mice
.
Pharmacol. Res.
128
,
18
28
[PubMed]
20.
Watanabe
M.
,
Suliman
M.E.
,
Qureshi
A.R.
,
Garcia-Lopez
E.
,
Barany
P.
,
Heimburger
O.
et al. .
(
2008
)
Consequences of low plasma histidine in chronic kidney disease patients: associations with inflammation, oxidative stress, and mortality
.
Am. J. Clin. Nutr.
87
,
1860
1866
[PubMed]
21.
Flancbaum
L.
,
Fitzpatrick
J.C.
,
Brotman
D.N.
,
Marcoux
A.M.
,
Kasziba
E.
and
Fisher
H.
(
1990
)
The presence and significance of carnosine in histamine-containing tissues of several mammalian species
.
Agents Actions
31
,
190
196
[PubMed]
22.
Riedl
E.
,
Pfister
F.
,
Braunagel
M.
,
Brinkkotter
P.
,
Sternik
P.
,
Deinzer
M.
et al. .
(
2011
)
Carnosine prevents apoptosis of glomerular cells and podocyte loss in STZ diabetic rats
.
Cell. Physiol. Biochem.
279
288
23.
Hipkiss
A.R.
(
2005
)
Glycation, ageing and carnosine: are carnivorous diets beneficial?
Mech. Ageing Dev.
126
,
1034
1039
[PubMed]
24.
Torres
V.E.
,
Northrup
T.E.
,
Edwards
R.M.
,
Shah
S.V.
and
Dousa
T.P.
(
1978
)
Modulation of cyclic nucleotides in islated rat glomeruli: role of histamine, carbamylcholine, parathyroid hormone, and angiotensin-II
.
J. Clin. Invest.
62
,
1334
1343
[PubMed]
25.
Rosa
A.C.
,
Grange
C.
,
Pini
A.
,
Katebe
M.A.
,
Benetti
E.
,
Collino
M.
et al. .
(
2013
)
Overexpression of histamine H(4) receptors in the kidney of diabetic rat
.
Inflamm. Res.
62
,
357
365
26.
Pini
A.
,
Chazot
P.L.
,
Veglia
E.
,
Moggio
A.
and
Rosa
A.C.
(
2015
)
H3 receptor renal expression in normal and diabetic rats
.
Inflamm. Res.
64
,
271
273
27.
Veglia
E.
,
Grange
C.
,
Pini
A.
,
Moggio
A.
,
Lanzi
C.
,
Camussi
G.
et al. .
(
2015
)
Histamine receptor expression in human renal tubules: a comparative pharmacological evaluation
.
Inflamm. Res.
64
,
261
270
28.
Pecis
M.
,
Azevedo
M.J.
and
Gross
J.L.
(
1997
)
Glomerular hyperfiltration is associated with blood pressure abnormalities in normotensive normoalbuminuric IDDM patients
.
Diabetes Care
20
,
1329
1333
[PubMed]
29.
Cherney
D.Z.
,
Miller
J.A.
,
Scholey
J.W.
,
Nasrallah
R.
,
Hebert
R.L.
,
Dekker
M.G.
et al. .
(
2010
)
Renal hyperfiltration is a determinant of endothelial function responses to cyclooxygenase 2 inhibition in type 1 diabetes
.
Diabetes Care
33
,
1344
1346
[PubMed]
30.
Cherney
D.Z.
,
Sochett
E.B.
,
Lai
V.
,
Dekker
M.G.
,
Slorach
C.
,
Scholey
J.W.
et al. .
(
2010
)
Renal hyperfiltration and arterial stiffness in humans with uncomplicated type 1 diabetes
.
Diabetes Care
33
,
2068
2070
[PubMed]
31.
Lewis
T.
and
Grant
R.T.
(
1924
)
Vascular reactions of the skin to injury
.
Lancet North Am. Ed.
204
,
279
280
32.
Hollis
T.M.
,
Kern
J.A.
,
Enea
N.A.
and
Cosgarea
A.J.
(
1985
)
Changes in plasma histamine concentration in the streptozotocin-diabetic rat
.
Exp. Mol. Pathol.
43
,
90
96
[PubMed]
33.
Orlidge
A.
and
Hollis
T.M.
(
1982
)
Aortic endothelial and smooth muscle histamine metabolism in experimental diabetes
.
Arteriosclerosis
2
,
142
150
[PubMed]
34.
Hollis
T.M.
and
Strickberger
S.A.
(
1985
)
Inhibition of aortic histamine synthesis by alpha-hydrazinohistidine inhibits increased aortic albumin accumulation in experimental diabetes in the rat
.
Diabetologia
28
,
282
285
[PubMed]
35.
Zdravkovic
V.
,
Pantovic
S.
,
Rosic
G.
,
Tomic-Lucic
A.
,
Zdravkovic
N.
,
Colic
M.
et al. .
(
2011
)
Histamine blood concentration in ischemic heart disease patients
.
J. Biomed. Biotechnol.
2011
,
315709
[PubMed]
36.
Mukai
N.
,
Hori
S.
and
Pomeroy
M.
(
1980
)
Cerebral lesions in rats with streptozotocin-induced diabetes
.
Acta Neuropathol. (Berl)
51
,
79
84
37.
Stauber
W.T.
,
Ong
S.H.
and
McCuskey
R.S.
(
1981
)
Selective extravascular escape of albumin into the cerebral cortex of the diabetic rat
.
Diabetes
30
,
500
503
[PubMed]
38.
McCuskey
P.A.
and
McCuskey
R.S.
(
1984
)
In vivo and electron microscopic study of the development of cerebral diabetic microangiography
.
Microcirc. Endothelium Lymphatics
1
,
221
244
[PubMed]
39.
Lorenzi
M.
,
Healy
D.P.
,
Hawkins
R.
,
Printz
J.M.
and
Printz
M.P.
(
1986
)
Studies on the permeability of the blood-brain barrier in experimental diabetes
.
Diabetologia
29
,
58
62
[PubMed]
40.
Yousif
K.
,
Bebbington
J.
and
Foley
B.
(
2005
)
Impact on patients triage distribution utilizing the Australasian Triage Scale compared with its predecessor the National Triage Scale
.
Emerg. Med. Austr.
17
,
429
433
[PubMed]
41.
Carmines
P.K.
(
2010
)
The renal vascular response to diabetes
.
Curr. Opin. Nephrol. Hypertens.
19
,
85
90
[PubMed]
42.
Wigg
S.J.
,
Tare
M.
,
Tonta
M.A.
,
O’Brien
R.C.
,
Meredith
I.T.
and
Parkington
H.C.
(
2001
)
Comparison of effects of diabetes mellitus on an EDHF-dependent and an EDHF-independent artery
.
Am. J. Physiol. Heart Circ. Physiol.
281
,
H232
H240
43.
Burnham
M.P.
,
Johnson
I.T.
and
Weston
A.H.
(
2006
)
Reduced Ca2+-dependent activation of large-conductance Ca2+-activated K+ channels from arteries of Type 2 diabetic Zucker diabetic fatty rats
.
Am. J. Physiol. Heart Circ. Physiol.
290
,
H1520
H1527
44.
Leo
C.H.
,
Hart
J.L.
and
Woodman
O.L.
(
2011
)
3′,4′-Dihydroxyflavonol reduces superoxide and improves nitric oxide function in diabetic rat mesenteric arteries
.
PLoS ONE
6
,
e20813
[PubMed]
45.
Zhao
L.M.
,
Wang
Y.
,
Yang
Y.
,
Guo
R.
,
Wang
N.P.
and
Deng
X.L.
(
2014
)
Metformin restores intermediate-conductance calcium-activated K(+) channel- and small-conductance calcium-activated K(+) channel-mediated vasodilatation impaired by advanced glycation end products in rat mesenteric artery
.
Mol. Pharmacol.
86
,
580
591
[PubMed]
46.
Brenner
B.M.
,
Lawler
E.V.
and
Mackenzie
H.S.
(
1996
)
The hyperfiltration theory: a paradigm shift in nephrology
.
Kidney Int.
49
,
1774
1777
[PubMed]
47.
Banks
R.O.
,
Inscho
E.W.
and
Jacobson
E.D.
(
1984
)
Histamine H1 receptor antagonists inhibit autoregulation of renal blood flow in the dog
.
Circ. Res.
54
,
527
535
[PubMed]
48.
Palatini
P.
(
2012
)
Glomerular hyperfiltration: a marker of early renal damage in pre-diabetes and pre-hypertension
.
Nephrol. Dial. Transplant.
27
,
1708
1714
49.
Killackey
J.J.
,
Johnston
M.G.
and
Movat
H.Z.
(
1986
)
Increased permeability of microcarrier-cultured endothelial monolayers in response to histamine and thrombin. A model for the in vitro study of increased vasopermeability
.
Am. J. Pathol.
122
,
50
61
[PubMed]
50.
Rotrosen
D.
and
Gallin
J.I.
(
1986
)
Histamine type I receptor occupancy increases endothelial cytosolic calcium, reduces F-actin, and promotes albumin diffusion across cultured endothelial monolayers
.
J. Cell Biol.
103
,
2379
2387
[PubMed]
51.
Hamilton
K.K.
and
Sims
P.J.
(
1987
)
Changes in cytosolic Ca2+ associated with von Willebrand factor release in human endothelial cells exposed to histamine. Study of microcarrier cell monolayers using the fluorescent probe indo-1
.
J. Clin. Invest.
79
,
600
608
[PubMed]
52.
Brock
T.A.
and
Capasso
E.A.
(
1988
)
Thrombin and histamine activate phospholipase C in human endothelial cells via a phorbol ester-sensitive pathway
.
J. Cell. Physiol.
136
,
54
62
[PubMed]
53.
Carson
M.R.
,
Shasby
S.S.
and
Shasby
D.M.
(
1989
)
Histamine and inositol phosphate accumulation in endothelium: cAMP and a G protein
.
Am. J. Physiol.
257
,
L259
L264
[PubMed]
54.
Niimi
N.
,
Noso
N.
and
Yamamoto
S.
(
1992
)
The effect of histamine on cultured endothelial cells. A study of the mechanism of increased vascular permeability
.
Eur. J. Pharmacol.
221
,
325
331
[PubMed]
55.
Gardner
T.W.
,
Lesher
T.
,
Khin
S.
,
Vu
C.
,
Barber
A.J.
and
Brennan
W.A.
Jr
(
1996
)
Histamine reduces ZO-1 tight-junction protein expression in cultured retinal microvascular endothelial cells
.
Biochem. J.
320
,
717
721
[PubMed]
56.
Gardner
T.W.
(
1995
)
Histamine, ZO-1 and increased blood-retinal barrier permeability in diabetic retinopathy
.
Trans. Am. Ophthalmol. Soc.
93
,
583
621
[PubMed]
57.
Gardner
T.W.
,
Lieth
E.
,
Antonetti
A.
and
Berber
A.J.
(
1998
)
A new hypothesis on mechanism of retinal vascular permeability in diabetes
. In
Diabetic Renal-Retinal Syndrome
(
Friedman
E.A.
and
L’Esperance
F.A.J.
, eds), pp.
169
179
,
Springer
,
Netherlands
58.
Gardner
T.W.
,
Sander
B.
,
Larsen
M.L.
,
Kunselman
A.
,
Tenhave
T.
,
Lund-Andersen
H.
et al. .
(
2006
)
An extension of the Early Treatment Diabetic Retinopathy Study (ETDRS) system for grading of diabetic macular edema in the Astemizole Retinopathy Trial
.
Curr. Eye Res.
31
,
535
547
[PubMed]
59.
Anbar
H.S.
,
Shehatou
G.S.
,
Suddek
G.M.
and
Gameil
N.M.
(
2016
)
Comparison of the effects of levocetirizine and losartan on diabetic nephropathy and vascular dysfunction in streptozotocin-induced diabetic rats
.
Eur. J. Pharmacol.
780
,
82
92
[PubMed]
60.
Ichikawa
I.
and
Brenner
B.M.
(
1979
)
Mechanisms of action of hisamine and histamine antagonists on the glomerular microcirculation in the rat
.
Circ. Res.
45
,
737
745
[PubMed]
61.
Wilson
N.K.
,
Chuang
J.C.
,
Morgan
M.K.
,
Lordo
R.A.
and
Sheldon
L.S.
(
2007
)
An observational study of the potential exposures of preschool children to pentachlorophenol, bisphenol-A, and nonylphenol at home and daycare
.
Environ. Res.
103
,
9
20
[PubMed]
62.
Tang
S.C.
and
Lai
K.N.
(
2012
)
The pathogenic role of the renal proximal tubular cell in diabetic nephropathy
.
Nephrol. Dial. Transplant.
27
,
3049
3056
63.
Zheng
Z.
and
Zheng
F.
(
2016
)
Immune cells and inflammation in diabetic nephropathy
.
J. Diabetes Res.
2016
,
1841690
[PubMed]
64.
Lim
A.K.
and
Tesch
G.H.
(
2012
)
Inflammation in diabetic nephropathy
.
Mediators Inflamm.
2012
,
146154
[PubMed]
65.
Zampeli
E.
and
Tiligada
E.
(
2009
)
The role of histamine H4 receptor in immune and inflammatory disorders
.
Br. J. Pharmacol.
157
,
24
33
[PubMed]
66.
Bakker
R.A.
,
Schoonus
S.B.
,
Smit
M.J.
,
Timmerman
H.
and
Leurs
R.
(
2001
)
Histamine H(1)-receptor activation of nuclear factor-kappa B: roles for G beta gamma- and G alpha(q/11)-subunits in constitutive and agonist-mediated signaling
.
Mol. Pharmacol.
60
,
1133
1142
[PubMed]
67.
Grosicki
M.
,
Wojcik
T.
,
Chlopicki
S.
and
Kiec-Kononowicz
K.
(
2016
)
In vitro study of histamine and histamine receptor ligands influence on the adhesion of purified human eosinophils to endothelium
.
Eur. J. Pharmacol.
777
,
49
59
[PubMed]
68.
Ling
P.
,
Ngo
K.
,
Nguyen
S.
,
Thurmond
R.L.
,
Edwards
J.P.
,
Karlsson
L.
et al. .
(
2004
)
Histamine H4 receptor mediates eosinophil chemotaxis with cell shape change and adhesion molecule upregulation
.
Br. J. Pharmacol.
142
,
161
171
[PubMed]
69.
Godot
V.
,
Arock
M.
,
Garcia
G.
,
Capel
F.
,
Flys
C.
,
Dy
M.
et al. .
(
2007
)
H4 histamine receptor mediates optimal migration of mast cell precursors to CXCL12
.
J. Allergy Clin. Immunol.
120
,
827
834
[PubMed]
70.
Dai
D.F.
,
Sasaki
K.
,
Lin
M.Y.
,
Smith
K.D.
,
Nicosia
R.F.
,
Alpers
C.E.
et al. .
(
2015
)
Interstitial eosinophilic aggregates in diabetic nephropathy: allergy or not?
Nephrol. Dial. Transplant. Renal Assoc.
30
,
1370
1376
71.
Busse
W.W.
and
Sosman
J.
(
1976
)
Histamine inhibition of neutrophil lysosomal enzyme release: an H2 histamine receptor response
.
Science
194
,
737
738
[PubMed]
72.
Ferstl
R.
,
Akdis
C.A.
and
O’Mahony
L.
(
2012
)
Histamine regulation of innate and adaptive immunity
.
Front. Biosci.
17
,
40
53
73.
Li
H.
,
Guo
D.
,
Zhang
L.
and
Feng
X.
(
2018
)
Glycyrrhizin attenuates histamine-mediated MUC5AC upregulation, inflammatory cytokine production, and aquaporin 5 downregulation through suppressing the NF-kappaB pathway in human nasal epithelial cells
.
Chem. Biol. Interact.
285
,
21
26
[PubMed]
74.
Charlesworth
E.N.
,
Kagey-Sobotka
A.
,
Norman
P.S.
and
Lichtenstein
L.M.
(
1989
)
Effect of cetirizine on mast cell-mediator release and cellular traffic during the cutaneous late-phase reaction
.
J. Allergy Clin. Immunol.
83
,
905
912
[PubMed]
75.
Jinquan
T.
,
Reimert
C.M.
,
Deleuran
B.
,
Zachariae
C.
,
Simonsen
C.
and
Thestrup-Pedersen
K.
(
1995
)
Cetirizine inhibits the in vitro and ex vivo chemotactic response of T lymphocytes and monocytes
.
J. Allergy Clin. Immunol.
95
,
979
986
[PubMed]
76.
Arnold
R.
,
Rihoux
J.
and
Konig
W.
(
1999
)
Cetirizine counter-regulates interleukin-8 release from human epithelial cells (A549)
.
Clin. Exp. Allergy
29
,
1681
1691
77.
Shimizu
T.
,
Nishihira
J.
,
Watanabe
H.
,
Abe
R.
,
Ishibashi
T.
and
Shimizu
H.
(
2004
)
Cetirizine, an H1-receptor antagonist, suppresses the expression of macrophage migration inhibitory factor: its potential anti-inflammatory action
.
Clin. Exp. Allergy
34
,
103
109
78.
Shankar
A.
,
Sun
L.
,
Klein
B.E.
,
Lee
K.E.
,
Muntner
P.
,
Nieto
F.J.
et al. .
(
2011
)
Markers of inflammation predict the long-term risk of developing chronic kidney disease: a population-based cohort study
.
Kidney Int.
80
,
1231
1238
[PubMed]
79.
Pruijm
M.
,
Ponte
B.
,
Vollenweider
P.
,
Mooser
V.
,
Paccaud
F.
,
Waeber
G.
et al. .
(
2012
)
Not all inflammatory markers are linked to kidney function: results from a population-based study
.
Am. J. Nephrol.
35
,
288
294
[PubMed]
80.
Duran-Salgado
M.B.
and
Rubio-Guerra
A.F.
(
2014
)
Diabetic nephropathy and inflammation
.
World J. Diabetes
5
,
393
398
81.
Kohka
H.
,
Nishibori
M.
,
Iwagaki
H.
,
Nakaya
N.
,
Yoshino
T.
,
Kobashi
K.
et al. .
(
2000
)
Histamine is a potent inducer of IL-18 and IFN-gamma in human peripheral blood mononuclear cells
.
J. Immunol.
164
,
6640
6646
[PubMed]
82.
Takahashi
H.K.
,
Yoshida
A.
,
Iwagaki
H.
,
Yoshino
T.
,
Itoh
H.
,
Morichika
T.
et al. .
(
2002
)
Histamine regulation of interleukin-18-initiating cytokine cascade is associated with down-regulation of intercellular adhesion molecule-1 expression in human peripheral blood mononuclear cells
.
J. Pharmacol. Exp. Ther.
300
,
227
235
[PubMed]
83.
Ramseyer
V.D.
and
Garvin
J.L.
(
2013
)
Tumor necrosis factor-alpha: regulation of renal function and blood pressure
.
Am. J. Physiol. Renal Physiol.
304
,
F1231
42
84.
Im
S.J.
,
Ahn
M.H.
,
Han
I.H.
,
Song
H.O.
,
Kim
Y.S.
,
Kim
H.M.
et al. .
(
2011
)
Histamine and TNF-alpha release by rat peritoneal mast cells stimulated with Trichomonas vaginalis
.
Parasite
18
,
49
55
[PubMed]
85.
Maurer
M.
,
Opitz
M.
,
Henz
B.M.
and
Paus
R.
(
1997
)
The mast cell products histamine and serotonin stimulate and TNF-alpha inhibits the proliferation of murine epidermal keratinocytes in situ
.
J. Dermatol. Sci.
16
,
79
84
[PubMed]
86.
Wang
J.
,
Al-Lamki
R.S.
,
Zhang
H.
,
Kirkiles-Smith
N.
,
Gaeta
M.L.
,
Thiru
S.
et al. .
(
2003
)
Histamine antagonizes tumor necrosis factor (TNF) signaling by stimulating TNF receptor shedding from the cell surface and Golgi storage pool
.
J. Biol. Chem.
278
,
21751
21760
[PubMed]
87.
Vannier
E.
,
Miller
L.C.
and
Dinarello
C.A.
(
1991
)
Histamine suppresses gene expression and synthesis of tumor necrosis factor alpha via histamine H2 receptors
.
J. Exp. Med.
174
,
281
284
[PubMed]
88.
Steffel
J.
,
Akhmedov
A.
,
Greutert
H.
,
Luscher
T.F.
and
Tanner
F.C.
(
2005
)
Histamine induces tissue factor expression: implications for acute coronary syndromes
.
Circulation
112
,
341
349
[PubMed]
89.
Steffel
J.
,
Arnet
C.
,
Akhmedov
A.
,
Iseli
S.M.
,
Luscher
T.F.
and
Tanner
F.C.
(
2006
)
Histamine differentially interacts with tumor necrosis factor-alpha and thrombin in endothelial tissue factor induction: the role of c-Jun NH2-terminal kinase
.
J. Thromb. Haemost.
4
,
2452
2460
90.
Li
F.
,
Wang
C.H.
,
Wang
J.G.
,
Thai
T.
,
Boysen
G.
,
Xu
L.
et al. .
(
2010
)
Elevated tissue factor expression contributes to exacerbated diabetic nephropathy in mice lacking eNOS fed a high fat diet
.
J. Thromb. Haemost.
8
,
2122
2132
91.
Lee
S.B.
and
Kalluri
R.
(
2010
)
Mechanistic connection between inflammation and fibrosis
.
Kidney Int. Suppl.
119
,
S22
S26
92.
Ferenbach
D.
,
Kluth
D.C.
and
Hughes
J.
(
2007
)
Inflammatory cells in renal injury and repair
.
Semin. Nephrol.
27
,
250
259
[PubMed]
93.
Lopez-Perra
V.
,
Mallavia
B.
,
Egido
J.
and
Gomez-Guerrero
C.
(
2012
)
Immunoinflammation in diabetic nephropathy: molecular mechanisms and therapeutic options
. In
Diabetic Nephropathy
(
Chan
J.
, ed.), pp.
127
146
,
InTech
94.
Triggiani
M.
,
Petraroli
A.
,
Loffredo
S.
,
Frattini
A.
,
Granata
F.
,
Morabito
P.
et al. .
(
2007
)
Differentiation of monocytes into macrophages induces the upregulation of histamine H1 receptor
.
J. Allergy Clin. Immunol.
119
,
472
481
[PubMed]
95.
Czerner
C.P.
,
Klos
A.
,
Seifert
R.
and
Neumann
D.
(
2014
)
Histamine induces chemotaxis and phagocytosis in murine bone marrow-derived macrophages and RAW 264.7 macrophage-like cells via histamine H4-receptor
.
Inflamm. Res.
63
,
239
247
96.
Zwadlo-Klarwasser
G.
,
Braam
U.
,
Muhl-Zurbes
P.
and
Schmutzler
W.
(
1994
)
Macrophages and lymphocytes: alternative sources of histamine
.
Agents Actions
41
,
Suppl. 1
,
C99
C100
,
97.
El Mesallamy
H.O.
,
Ahmed
H.H.
,
Bassyouni
A.A.
and
Ahmed
A.S.
(
2012
)
Clinical significance of inflammatory and fibrogenic cytokines in diabetic nephropathy
.
Clin. Biochem.
45
,
646
650
[PubMed]
98.
Fan
J.M.
,
Ng
Y.Y.
,
Hill
P.A.
,
Nikolic-Paterson
D.J.
,
Mu
W.
,
Atkins
R.C.
et al. .
(
1999
)
Transforming growth factor-beta regulates tubular epithelial-myofibroblast transdifferentiation in vitro
.
Kidney Int.
56
,
1455
1467
[PubMed]
99.
Oldfield
M.D.
,
Bach
L.A.
,
Forbes
J.M.
,
Nikolic-Paterson
D.
,
McRobert
A.
,
Thallas
V.
et al. .
(
2001
)
Advanced glycation end products cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products (RAGE)
.
J. Clin. Invest.
108
,
1853
1863
[PubMed]
100.
Gewin
L.
and
Zent
R.
(
2012
)
How does TGF-beta mediate tubulointerstitial fibrosis?
Semin. Nephrol.
32
,
228
235
[PubMed]
101.
Chakraborty
S.
,
Chopra
P.
,
Ambi
S.V.
,
Dastidar
S.G.
and
Ray
A.
(
2014
)
Emerging therapeutic interventions for idiopathic pulmonary fibrosis
.
Expert Opin. Investig. Drugs
23
,
893
910
[PubMed]
102.
Trachtman
H.
,
Fervenza
F.C.
,
Gipson
D.S.
,
Heering
P.
,
Jayne
D.R.
,
Peters
H.
et al. .
(
2011
)
A phase 1, single-dose study of fresolimumab, an anti-TGF-beta antibody, in treatment-resistant primary focal segmental glomerulosclerosis
.
Kidney Int.
79
,
1236
1243
[PubMed]
103.
Rosa
A.C.
,
Pini
A.
,
Lucarini
L.
,
Lanzi
C.
,
Veglia
E.
,
Thurmond
R.L.
et al. .
(
2014
)
Prevention of bleomycin-induced lung inflammation and fibrosis in mice by naproxen and JNJ7777120 treatment
.
J. Pharmacol. Exp. Ther.
351
,
308
316
[PubMed]
104.
Lucarini
L.
,
Pini
A.
,
Rosa
A.C.
,
Lanzi
C.
,
Durante
M.
,
Chazot
P.L.
et al. .
(
2016
)
Role of histamine H4 receptor ligands in bleomycin-induced pulmonary fibrosis
.
Pharmacol. Res.
111
,
740
748
[PubMed]
105.
Meng
X.M.
,
Huang
X.R.
,
Chung
A.C.
,
Qin
W.
,
Shao
X.
,
Igarashi
P.
et al. .
(
2010
)
Smad2 protects against TGF-beta/Smad3-mediated renal fibrosis
.
J. Am. Soc. Nephrol.
21
,
1477
1487
106.
Lan
H.Y.
(
2011
)
Diverse roles of TGF-beta/Smads in renal fibrosis and inflammation
.
Int. J. Biol. Sci.
7
,
1056
1067
[PubMed]
107.
Lan
H.Y.
and
Chung
A.C.
(
2012
)
TGF-beta/Smad signaling in kidney disease
.
Semin. Nephrol.
32
,
236
243
[PubMed]
108.
Meng
X.M.
,
Chung
A.C.
and
Lan
H.Y.
(
2013
)
Role of the TGF-beta/BMP-7/Smad pathways in renal diseases
.
Clin. Sci.
124
,
243
254
[PubMed]
109.
Silver
R.B.
(
2013
)
Role of mast cells in renal fibrosis
.
Kidney Int.
84
,
214
[PubMed]
110.
Zeni
L.
,
Norden
A.G.W.
,
Cancarini
G.
and
Unwin
R.J.
(
2017
)
A more tubulocentric view of diabetic kidney disease
.
J. Nephrol.
30
,
701
717
[PubMed]
111.
Persson
A.E.
and
Wright
F.S.
(
1982
)
Evidence for feedback mediated reduction of glomerular filtration rate during infusion of acetazolamide
.
Acta Physiol. Scand.
114
,
1
7
[PubMed]
112.
Dickson
L.E.
,
Wagner
M.C.
,
Sandoval
R.M.
and
Molitoris
B.A.
(
2014
)
The proximal tubule and albuminuria: really!
.
J. Am. Soc. Nephrol.
25
,
443
453
113.
Tojo
A.
,
Onozato
M.L.
,
Ha
H.
,
Kurihara
H.
,
Sakai
T.
,
Goto
A.
et al. .
(
2001
)
Reduced albumin reabsorption in the proximal tubule of early-stage diabetic rats
.
Histochem. Cell Biol.
116
,
269
276
[PubMed]
114.
Russo
L.M.
,
Sandoval
R.M.
,
Campos
S.B.
,
Molitoris
B.A.
,
Comper
W.D.
and
Brown
D.
(
2009
)
Impaired tubular uptake explains albuminuria in early diabetic nephropathy
.
J. Am. Soc. Nephrol.
20
,
489
494
115.
Amsellem
S.
,
Gburek
J.
,
Hamard
G.
,
Nielsen
R.
,
Willnow
T.E.
,
Devuyst
O.
et al. .
(
2010
)
Cubilin is essential for albumin reabsorption in the renal proximal tubule
.
J. Am. Soc. Nephrol.
21
,
1859
1867
116.
Mori
K.P.
,
Yokoi
H.
,
Kasahara
M.
,
Imamaki
H.
,
Ishii
A.
,
Kuwabara
T.
et al. .
(
2017
)
Increase of total nephron albumin filtration and reabsorption in diabetic nephropathy
.
J. Am. Soc. Nephrol.
28
,
278
289
117.
Girardi
A.C.
and
Di Sole
F.
(
2012
)
Deciphering the mechanisms of the Na+/H+ exchanger-3 regulation in organ dysfunction
.
Am. J. Physiol. Cell Physiol.
302
,
C1569
C1587
[PubMed]
118.
Zerbini
G.
,
Gabellini
D.
,
Maestroni
S.
and
Maestroni
A.
(
2007
)
Early renal dysfunctions in type 1 diabetes and pathogenesis of diabetic nephropathy
.
J. Nephrol.
20
(
Suppl. 12
),
S19
S22
[PubMed]
119.
Queiroz-Leite
G.D.
,
Peruzzetto
M.C.
,
Neri
E.A.
and
Reboucas
N.A.
(
2011
)
Transcriptional regulation of the Na(+)/H(+) exchanger NHE3 by chronic exposure to angiotensin II in renal epithelial cells
.
Biochem. Biophys. Res. Commun.
409
,
470
476
[PubMed]
120.
Rossi
L.
,
Nicoletti
M.C.
,
Carmosino
M.
,
Mastrofrancesco
L.
,
Di Franco
A.
,
Indrio
F.
et al. .
(
2017
)
Urinary excretion of kidney aquaporins as possible diagnostic biomarker of diabetic nephropathy
.
J. Diabetes Res.
2017
,
4360357
[PubMed]
121.
Wang
W.
,
Wang
X.
,
Ma
L.
and
Zhang
R.
(
2015
)
Histamine downregulates aquaporin 5 in human nasal epithelial cells
.
Am. J. Rhinol. Allergy
29
,
188
192
[PubMed]
122.
Chang
Y.L.
,
Lin
C.S.
,
Wang
H.W.
,
Jian
K.R.
and
Liu
S.C.
(
2017
)
Chlorpheniramine attenuates histamine-mediated aquaporin 5 downregulation in human nasal epithelial cells via suppression of NF-kappaB activation
.
Int. J. Med. Sci.
14
,
1268
1275
[PubMed]
123.
Kim
J.H.
,
Park
S.H.
,
Moon
Y.W.
,
Hwang
S.
,
Kim
D.
,
Jo
S.H.
et al. .
(
2009
)
Histamine H1 receptor induces cytosolic calcium increase and aquaporin translocation in human salivary gland cells
.
J. Pharmacol. Exp. Ther.
330
,
403
412
[PubMed]
124.
Carmosino
M.
,
Procino
G.
,
Nicchia
G.P.
,
Mannucci
R.
,
Verbavatz
J.M.
,
Gobin
R.
et al. .
(
2001
)
Histamine treatment induces rearrangements of orthogonal arrays of particles (OAPs) in human AQP4-expressing gastric cells
.
J. Cell Biol.
154
,
1235
1243
[PubMed]
125.
Pini
A.
,
Obara
I.
,
Battell
E.
,
Chazot
P.L.
and
Rosa
A.C.
(
2016
)
Histamine in diabetes: is it time to reconsider?
Pharmacol. Res.
111
,
316
324

Author notes

*

These authors contributed equally to this work.