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JAK inhibition and progressive kidney disease

Brosius, Frank C. IIIa; He, John Cijiangb

Current Opinion in Nephrology and Hypertension: January 2015 - Volume 24 - Issue 1 - p 88–95
doi: 10.1097/MNH.0000000000000079

Purpose of review To review the role of Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling in the progression of chronic kidney diseases.

Recent findings The JAK-STAT pathway transmits signals from extracellular ligands, including many cytokines and chemokines. While these responses are best characterized in lymphoid cells, they also occur in kidney cells such as podocytes, mesangial cells, and tubular cells. JAK-STAT expression and signaling abnormalities occur in humans and animal models of different chronic kidney diseases. Enhanced expression and augmented activity of JAK1, JAK2, and STAT3 promote diabetic nephropathy and their inhibition appears to reduce the disease. Activation of JAK-STAT signaling in autosomal dominant polycystic kidney disease may play an important role in cyst growth. Activation of JAK-STAT signaling promotes HIV-associated nephropathy and may also participate in the tubular responses to chronic obstructive uropathy. On the basis of data from experimental models, inhibition of JAK-STAT signaling, via increased expression of the suppressors of cytokine signaling proteins or pharmacologic inhibition of JAK and STAT proteins, could play a therapeutic role in multiple chronic kidney diseases.

Summary Activation of the JAK-STAT pathway appears to play a role in the progression of some chronic kidney diseases. More work is needed to determine the specific role the pathway plays in individual diseases.

aDepartments of Internal Medicine and Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA

bDepartment of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Correspondence to Frank C. Brosius, University of Michigan, 5520 MSRB1, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-5680, USA. Tel: +1 734 936 5645; fax: +1 734 764 3151; e-mail:

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Many signaling pathways have been shown to be involved in the progression of chronic kidney disease (CKD) in humans and in animal models, usually due to persistent activation of these pathways. Perhaps the most well-known of such pathways include certain protein kinase pathways, such as protein kinase C [1] and mitogen-activated kinase pathways [2], which lead to cellular growth and fibrosis, and those such as angiotensin II [3] and transforming growth factor beta (TGF-ß)/SMAD [4] signaling pathways, which enhance fibrosis leading to kidney scarring. In addition, it has become increasingly clear over the past decade that many progressive kidney diseases are also characterized by sustained inflammation which appears to promote and direct much of the chronic injury process [5].

One of the major pathways that responds to and transduces inflammatory signals is the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. The JAK-STAT pathway transmits signals from extracellular ligands, including many cytokines and chemokines, as well as growth factors and hormones, directly to the nucleus to induce a variety of cellular responses [6]. Although many of these responses are present and best characterized in lymphoid cells, they have also been reported in many other cell types including kidney parenchymal cells such as podocytes [7], mesangial cells [8], and tubular cells [7].

Given the role of JAK-STAT activation in response to cytokines and chemokines, and the unequivocal role of inflammation in promoting progressive kidney injury, it is not surprising that JAK-STAT activation is involved in the pathogenesis of CKD as well as of acute kidney injury. Curiously, however, until recently, there have been few published reports on JAK-STAT signaling in CKD, and only an incomplete and rather general outline of JAK-STAT activation in CKD can be currently sketched.

Box 1

Box 1

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JAK-STAT proteins transduce signals from many different types of nontyrosine kinase plasma membrane receptors. After binding of their ligands, these membrane receptors dimerize and thereby recruit pairs of JAK proteins to the intracellular receptor domains and activate them by inducing the tyrosine kinase activity of the JAKs via autophosphorylation. The activated JAKs then phosphorylate tyrosine residues on the intracellular domains of the receptors, which then serve as docking sites for STAT proteins through the binding of Src homology 2 (SH2) domains. After phosphorylation by the JAK proteins, the STAT proteins form hetero or homodimers, which translocate to the nucleus to induce the transcription of the target genes [9]. Separate from this classical activation process, STAT proteins can be phosphorylated and activated by other tyrosine kinases such as growth factor receptors and nonreceptor tyrosine kinases, and can be indirectly activated via G-protein-coupled receptors, polycystin 1 and intracellular oxidant species [10–12]. In addition, lysine acetylation of STAT proteins can cause STAT activation [13], bypassing or augmenting the effects of JAK-induced phosphorylation [13]. The JAK-STAT signaling pathway is negatively regulated by several processes including dephosphorylation, nuclear export, and negative endogenous regulators such as suppressors of cytokine signaling (SOCS) and protein inhibitor of activated STAT (PIAS) [14].

Four members of the JAK family (JAK1, JAK2, JAK3, and TYK2) have been identified in mammals [15,16]. Although JAK proteins are structurally related, their differences in activation and downstream effects allow a high degree of specificity. JAK1 is activated by the ligands binding to the class II receptors [interferon (IFN)-α/β, IFN-γ, interleukin (IL)-10] and the γc receptor (IL-2, IL-4, IL-7, IL-9, IL-15, IL-21). JAK2 is activated mostly by single chain receptors such as erythropoietin receptor (Epo) and thrombopoietin receptor (TPO), IL-3, granulocyte-macrophage colony stimulating factor (GM-CSF), and IFN-γ. Whereas the majority of JAKs are ubiquitously expressed, JAK3 expression appears to be generally restricted to hemopoietic lineages and vascular muscle cells, and JAK3 plays a critical role in lymphocyte development and function. Tyk2 mediates mostly signaling induced by IL-12. There are seven STATs in mammalian cells, STAT1–4, 5a, 5b, and 6. The role of individual STATs in the immune system and cancer are discussed below.

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Role of JAK-STAT signaling in immune cells, autoimmune diseases, and cancer

A large body of evidence suggests a critical role for JAKs and STATs in the differentiation and maturation of the immune system. Development of the Th1 response requires IL-12/STAT4, whereas the Th2 response requires IL-4/STAT6 [17]. However, recent data suggest that STAT3 and STAT5A/B are also involved in Th2 differentiation [18,19]. As the mediators of IL-2 signaling, STAT5A and B are also critical for the differentiation of Treg cells [20]. STAT3 is required for Th17 differentiation, mediating signals induced by IL-23 and IL-6 [21]. Interestingly, IL-2-induced STAT5A/B activation is an important negative regulator of Th17 differentiation [22]. STAT3 activation induced by IL-10 and IL-21 is important for CD8 function [23], and STAT5A/B activation induced by IL-7 is important in B-lymphocyte survival and development [24]. STATs also have numerous functions in innate immunity such as STAT1 in mediating IFN effects. STAT3 induced by IL-6 mediates pro-inflammatory effects, whereas STAT3 activated by IL-10 and IL-22 has anti-inflammatory properties [25]. Precisely, how STAT3 promotes inflammation in some circumstances and inhibits it in others remains unclear.

Numerous studies from animal models suggest a role for type I/II cytokine receptors and the JAK-STAT pathway in autoimmune diseases. These findings have been confirmed in humans by genetic studies [6]. Polymorphisms of the genes encoding IL-23, IL6R, JAK2, STAT3, and others have been linked to autoimmune processes such as inflammatory bowel disease [26,27]. These responses are complex and not easily predicted. For example, in contrast to the germline inactivating STAT3 mutations in hyper IgE syndrome, de-novo activating STAT3 mutations were recently reported as a cause of autoimmune diseases such as type 1 diabetes [28]. Multiple genes in the IL-12 pathway, including STAT4, are also associated with autoimmune diseases [29]. Polymorphisms of STAT6 and IL13 are associated with atopic dermatitis [30].

Activation of some JAK-STAT pathways also plays a major role in cancer and metastasis through regulation of cell proliferation, apoptosis, inflammation, and epithelial–mesenchymal transitions [31–35]. Certain JAK2 mutations, especially the V617F mutation, lead to JAK2 activation and development of polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Thus, compounds that inhibit JAK2 have been developed for their antineoplastic activities [35]. Among the STATs, activated STAT3 appears to be the predominant isoform in promoting cancers and is considered an oncogene [32]. Activation of STAT3 has been reported in a variety of human tumor cell lines and primary human tumors. In addition, lysine acetylation and resultant activation of STAT3 is elevated in tumors, and acetylated STAT3 induces methylation and inhibition of tumor-suppressor genes [36]. STAT3 not only induces tumor cell proliferation but also mediates angiogenesis and metastasis. STAT3 signaling is also a major pathway for cancer inflammation, whereas STAT1 increases antitumor immunity. Therefore, STAT3 has emerged as a crucial target for cancer therapy and STAT3 inhibitors are actively being developed [37].

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Advent of clinically useful JAK inhibitors

Since the JAK-STAT pathways play major activating roles in a variety of disease processes, there has been a robust effort to develop specific inhibitors of this pathway. As it is relatively easy to identify inhibitors of protein kinases; development of JAK inhibitors has received most attention. At present, two JAK inhibitors have received US Food and Drug Administration (FDA) approval for clinical use. Ruxolitinib (INCB018424, Jakafi, Incyte) is a potent inhibitor of both JAK1 and JAK2, and it received US FDA approval in November 2011 for the treatment of polycythemia vera and myelofibrosis [38]. Tofacitinib (CP690, 550, Xeljanz; Pfizer Inc., NY, USA) was initially designed to be a specific inhibitor of JAK3 kinase and therefore has been used as an immunosuppressant in transplantation and for the treatment of autoimmune diseases [39]. More recently, it was found that tofacitinib also inhibits JAK1 [40], which mediates IFN and IL-6-induced pro-inflammatory effects [41]. Tofacitinib received US FDA approval for the treatment of moderately to severely active rheumatoid arthritis in November 2012. Several other JAK inhibitors have been developed as either immunosuppressive agents or anticancer drugs. For example, baricitinib (a JAK1/2 inhibitor) and VX-509 (a specific JAK3 inhibitor) have been shown to be effective in the treatment of arthritis [41]. Therefore, it is likely that additional JAK inhibitors will become clinically available in the next few years.

Since STAT3 has a major role in tumorogenesis and inflammation, a number of efforts have been made to develop its inhibitors. There are several natural inhibitors of STAT3 and new synthetic blockers of STAT3 have also been made. However, after a decade of preclinical evaluation, only limited translational studies are currently in progress [42].

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The first evidence that JAK-STAT activation could be important in the pathogenesis of CKD came from Marrero et al.[11] in 1995 when direct activation of JAK-STAT signaling by angiotensin II was found in mesangial cells. Subsequent work by Marrero's group found evidence for JAK2 activation in mesangial cells exposed to high glucose concentrations in culture, and in diabetic rodent models, and that some of this activation was due to angiotensin II signaling [43,44]. These studies indicated that activation of TGF-β signaling and fibronectin production was at least partly mediated by JAK2 signaling. These downstream changes were abrogated by JAK2 inhibition [44,45] confirming that JAK2 activation was responsible for the effects. However, despite these interesting studies, few other investigations of the role of JAK-STAT signaling in diabetic kidney disease (DKD) were forthcoming until around 5 years ago.

In 2009, we reported that the mRNA expression of JAKs 1, 2, and 3, and STATs 1 and 3 was substantially increased in patients with DKD compared to normal individuals [7]. Expression was increased in glomeruli from patients with early nephropathy, but was increased in the tubulointerstitial region only in patients with progressive disease. This pattern corresponded to the natural pathologic progression of DKD, which also initially involves glomeruli and subsequently cortical tubulointerstitium. Indeed, the increased tubulointerstitial expression of all the JAK-STAT genes was tightly and inversely correlated to the decline in estimated glomerular filtration rate (GFR) in these patients [7]. A similar transcriptomic dataset was published by other investigators in a study of human patients with a variety of CKDs including diabetes [46]. In our analysis of this published dataset, we found that increases of JAK1, JAK2, STAT1, and STAT3 gene expression occurred in the subset of 22 patients with DKD compared to normal control individuals [47]. The implication from these two sets of studies is that increases in JAK-STAT gene expression result in increases in JAK-STAT activity, though this was not demonstrated in vivo.

Around the same time, Lu et al.[48] reported a transgenic mouse with a reduced capacity for STAT3 activation (Stat3SA/– mice) and found that Stat3SA/– animals with streptozotocin diabetes developed less proteinuria, mesangial expansion, cell proliferation, macrophage infiltration, inflammation, and abnormal matrix synthesis at an early stage of DKD. As would be expected from generalized increased JAK-STAT activation, downstream transcriptional targets of the JAK-STAT signaling pathway, suppressors of cytokine signaling (SOCS) genes, SOCS1 and SOCS3, have been shown to be activated in DKD in rodents and humans [49]. SOCS proteins bind to and interfere with initiating JAK proteins in a negative-feedback manner [50], serving to suppress the JAK-STAT signaling that triggers their expression. It appears that the highest expression of SOCS proteins is in proximal tubule epithelia, as well as in glomerular cells, in a similar distribution to that found for JAK2 in human DKD [7]. Rats injected with recombinant SOCS1 and SOCS3 adenovirus showed evidence for reduced JAK-STAT activation and some amelioration of early diabetic changes after 7 weeks of diabetes [49]. Additionally, injection of SOCS1 into the tail vein of mice with mild diabetic kidney disease reversed the increases in TGF-β and connective tissue growth factor in this model [51].

During the past 18 months, additional studies have shown evidence for JAK-STAT expression and activation in diabetic nephropathy. A transcriptomic analysis of Pima Indians with early DKD and of three good mouse models of nephropathy identified cross-species glomerular transcriptional networks shared between humans and mice that further defined gene networks involved in DKD. When similarities were mapped onto canonical signaling and metabolic pathways, more than one-third of the cross-species conserved pathways overlapped between all three human–mouse comparisons. The canonical pathway with the greatest degree of overlap was cytokine-induced JAK-STAT signaling [52▪]. Interestingly, this did not necessarily mean that there was an increased expression in JAK-STAT proteins themselves in the mouse models, but that there was evidence of increased gene expression downstream of STAT signaling. We have also published in preliminary form that podocyte-specific overexpression of JAK2 in mice to levels similar to that found in diabetic humans causes increased albuminuria, and mesangial expansion and sclerosis, as well as decreased podocyte density [53]. Baricitinib, the JAK1/2 inhibitor, is now being tested in phase 2 randomized clinical trials for efficacy in patients with diabetic nephropathy ( Identifier NCT01683409).

A very recent study showed that STAT3 acetylation was increased in both mouse and human diabetic kidneys [54▪]. Acteylation of STAT proteins can affect STAT dimerization which is critical for the translocation of STATs to the nucleus and their ability to modulate gene transcription [13]. In human podocytes, advanced glycation endproducts (AGEs) induced p65 and STAT3 acetylation and overexpression of acetylation-deficient mutants of p65 and STAT3 abrogated AGE-induced expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and STAT3 target genes. Inhibition of AGE formation in diabetic db/db mice by pyridoxamine treatment restored sirtuin 1 (SIRT1) expression, reduced p65 and STAT3 acetylation, and attenuated proteinuria and podocyte injury. Moreover, diabetic db/db mice with conditional deletion of SIRT1 in podocytes developed increased acetylation of p65 and STAT3, and enhanced proteinuria and kidney injury when compared to db/db mice without the SIRT1 deletion. Treatment with inhibitors that block acetylation-mediated association of p65 and STAT3 with BET proteins also attenuated proteinuria and kidney injury in db/db mice. These findings support a significant role for activated STAT3 acetylation in DKD. Perhaps, equally importantly, they show that podocyte STAT3 activation via acetylation can result in worsening nephropathy independent of upstream JAK signaling, or at least of changes in upstream JAK signaling. Thus, activation of podocyte JAK2 and podocyte STAT3 (with or without JAK2 activation) is important in the pathogenesis of DKD.

Finally, several studies confirmed the salutary effect of increasing SOCS expression in reducing DKD. Delivery of SOCS vectors systemically or directly into the kidney showed that increased expression of SOCS1 or SOCS3 [55], or of SOCS2 [56▪], can reduce some of the pathologic features of diabetic nephropathy in rodent models.

Figure 1 summarizes how the JAK-STAT pathway is activated in DKD.



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The JAK-STAT pathway has been extensively studied in autosomal dominant polycystic kidney disease (ADPKD) and nicely reviewed in a recent publication [57]. Polycystin 1 (PC1) was found to activate multiple JAK-STAT proteins in cyst-lining cells. Membrane-anchored PC1 interacts directly with JAK2 to activate STAT3 [12] while PC1 activates STAT6 through interaction with its C-terminal cytoplasmic tail released from the membrane by proteolytic cleavage [58]. Finally, the cleaved cytoplasmic tail of PC1 was recently shown to integrate signaling inputs from several pathways resulting in Src-dependent activation of STAT3 and the proliferative response in tubular cells [59▪▪]. This cytoplasmic tail cleavage appears to happen in response to injury and is turned on constitutively in ADPKD. STAT3 is strongly activated in cyst-lining cells in human ADPKD kidneys and four different PKD mouse models [12,57]. STAT3 may also mediate the effects of heme oxygenase on renal cyst growth [60]. In addition, STAT3 can also mediate macrophage activation and cytokine secretion in PKD [61]. Inhibition of STAT3 in PKD mouse models with different inhibitors has given promising results [62,63]. Even though the specificity of these compounds toward STAT3 is not well established, together, these studies suggest that STAT3 may be a highly promising therapeutic target for the treatment of PKD. STAT6 is also highly activated in cyst-lining cells in two different PKD mouse models [64]. Knockout of STAT6 led to a significant improvement in kidney function and decrease in cyst size [64]. STAT6 may mediate cyst formation and growth through regulation of macrophage function [61]. Overall, these studies provide strong evidence that the activation of the JAK-STAT pathway promotes proliferation of cyst-lining cells. Future studies are required to determine whether JAK-STAT inhibitors could be useful in the treatment of patients with ADPKD.

Unilateral ureteral obstruction (UUO) is a model of obstructive nephropathy that is commonly used to study renal fibrosis. Pang et al.[65] reported that STAT3 activity is involved in the activation and proliferation of interstitial fibroblasts in cultured cells and in the UUO model, and treatment of the UUO mice with a STAT3 inhibitor (S3I-201) attenuates fibrosis and inflammation in the UUO kidney. Recent studies from the same group demonstrate that inhibition of estimated GFR attenuates renal fibrosis, while STAT3 phosphorylation was also reduced in these mice [66]. However, in mice with knockout of SOC3 (SOCS3+/–), a negative regulator of JAK-STAT3, UUO-induced renal fibrosis was markedly suppressed. In addition, the renal fibrosis was aggravated in the UUO mice pretreated with a JAK inhibitor-incorporated nanoparticle (pyridine6-PGLA) [67]. The authors conclude that JAK-STAT3 signaling may play a role in repair process of renal fibrosis via matrix metalloproteinase-2 (MMP-2) activation [67]. The conflicting data from these studies suggest that JAK-STAT3 may have a dual role in renal fibrosis. It is also possible that activation of the JAK-STAT3 pathway in kidney tubular cells and fibroblasts may have different consequences for renal fibrosis. The role of STAT6 in the UUO model is more uncertain because STAT6−/− mice were shown to have enhanced apoptosis and inflammation, but less fibrosis, in the obstructed kidney [68]. Overall, the role of the JAK-STAT pathway in tubulointerstitial fibrosis remains controversial.

HIV-associated nephropathy (HIVAN) is characterized by collapsing focal segmental glomerulosclerosis, interstitial nephritis, and tubular microcystic dilatation. A distinctive feature of this disease is the finding of prominent hyperplasia of the glomerular cells leading to the formation of pseudocrescents. We have previously reported that STAT3 phosphorylation is significantly increased in the human kidney of HIVAN [69]. STAT3 is highly activated in HIVAN kidney by both viral protein Nef-induced Src and IL-6-induced JAK activation. Activation of STAT3 mediates multiple effects in HIVAN including promotion of podocyte proliferation, microcystic formation, and infiltration of inflammatory cells, and knockout of STAT3 either globally or specifically in kidney cells leads to a significant improvement of kidney injury in HIV-1 transgenic mice [70,71]. These studies suggest that STAT3 could be a potential target for the treatment of HIVAN.

Profiling of the kidney transcriptome in mice with ischemia–reperfusion injury revealed that the JAK-STAT pathway is highly enriched in the kidney with acute kidney injury (AKI) [72]. Exclusively, STAT3 was rapidly activated in injured renal tubule cells [12]. IL-6-induced STAT3 activation was observed in mice with HgCl2-induced AKI [73]. Experimental activation of STAT3 prior to HgCl2 administration protected animals from AKI. This effect was partially due to the induction of heme oxygenase-1 [73]. Several studies confirmed that animals with renal ischemia–reperfusion injury had increased expression of unphosphorylated STAT3 and activation of STAT3 [74,75]. Recent studies suggest that SOCS3 is highly expressed in renal proximal tubules during AKI. Conditional proximal tubular SOCS3 knockout mice maintained better kidney function than their littermates when kidney injury was induced by aristolochic acid or ischemia–reperfusion [76▪]. Thus, this study confirmed a protective role of STAT3 in AKI. A protective or reparative role of STAT6 was also observed in the kidney following acute injury. Following renal ischemia–reperfusion injury, STAT6−/− mice exhibited more severe tubular injury and worse renal function than did wild-type mice [77]. These studies suggest, in contrast to CKD, that the JAK-STAT pathway has a protective role in AKI through activation of STAT3 and STAT6.

In summary, activation of the JAK-STAT pathway plays a major role in a variety of non-DKDs. STAT3 and probably STAT6 are the most important isoforms involved in the pathogenesis of these kidney diseases. STAT3 is rapidly activated in response to several forms of renal insult and appears to be critical for the protection of kidney cells from acute injury. However, prolonged renal STAT3 activation appears to play a role in destructive processes such as persistent inflammation and fibrosis.

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Enhanced JAK-STAT expression and activation occur in a number of kidney diseases (Table 1). The isoforms that are most frequently regulated in kidney diseases are JAK2 and STAT3. Whereas increased JAK-STAT signaling appears to contribute to the pathogenesis of DKD, ADPKD, and HIVAN, it appears to play a protective role in AKI. In both DKD and AKI, expression of SOCS isoforms counteracts the effects of JAK-STAT activation. Enhancement of SOCS expression may help prevent pathologic changes of DKD. Further research to determine the precise role of JAK-STAT signaling and the effect of its inhibition on the progression of CKDs will be critical.

Table 1

Table 1

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Financial support and sponsorship

F.C.B. was supported by the Applied Systems Biology Core of the George O’Brien Kidney Core Center (NIH P30 DK081943) at the University of Michigan, by NIH grant R24 DK082841, and through research support from the A. Alfred Taubman Institute at the University of Michigan. J.C.H. was supported by a VA Merit Award, NIH 1R01DK078897, NIH 1R01DK088541, and NIH P01-DK-56492.

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Conflicts of interest

F.C.B. has accepted travel costs, but no honoraria, for consulting trips for Merck, Bristol Meyer Squibb, and Lilly and Co. As part of his University of Michigan appointment, he is principal investigator of a phase 2 clinical trial of a JAK1/2 inhibitor being conducted by Lilly and Co. J.C.H. declares no conflicts of interest.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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51. Shi Y, Du C, Zhang Y, et al. Suppressor of cytokine signaling-1 ameliorates expression of MCP-1 in diabetic nephropathy. Am J Nephrol 2010; 31:380–388.
52▪. Hodgin JB, Nair V, Zhang H, et al. Identification of cross-species shared transcriptional networks of diabetic nephropathy in human and mouse glomeruli. Diabetes 2013; 62:299–308.

This transcriptomic study showed increased evidence for enhanced expression and activation of JAK-STAT pathways in early diabetic glomerulopathy in both humans and three of the better mouse models of diabetic kidney disease.

53. Zhang H, Saha J, Atkins K, Brosius F III. Podocyte JAK2 augments glomerular injury induced by diabetes and angiotensin II. J Am Soc Nephrol 2012; 23:478A.
54▪. Liu R, Zhong Y, Li X, et al. Role of transcription factor acetylation in diabetic kidney disease. Diabetes 2014; 63:2440–2453.

This set of studies documented for the first time that STAT3 activation occurred via lysine acetylation that was enhanced by reduced SIRT1 activity in diabetic kidney disease. This presented a new paradigm, independent of enhanced JAK activation, by which diabetes leads to STAT3 activation and increased kidney pathology.

55. Liu Q, Xing L, Wang L, et al. Therapeutic effects of suppressors of cytokine signaling in diabetic nephropathy. J Histochem Cytochem 2014; 62:119–128.
56▪. Zhou Y, Lv C, Wu C, et al. Suppressor of cytokine signaling (SOCS) 2 attenuates renal lesions in rats with diabetic nephropathy. Acta Histochem 2014; 116:981–988.

Injection of SOCS2 adenovirus prevented the development of some early aspects of diabetic nephropathy in a rodent model.

57. Weimbs T, Olsan EE, Talbot JJ. Regulation of STATs by polycystin-1 and their role in polycystic kidney disease. JAKSTAT 2013; 2:e23650.
58. Low SH, Vasanth S, Larson CH, et al. Polycystin-1, STAT6, and P100 function in a pathway that transduces ciliary mechanosensation and is activated in polycystic kidney disease. Dev Cell 2006; 10:57–69.
59▪▪. Talbot JJ, Song X, Wang X, et al. The cleaved cytoplasmic tail of polycystin-1 regulates Src-dependent STAT3 activation. J Am Soc Nephrol 2014; 25:1737–1748.

In this study, the cleaved cytoplasmic tail of polycystin 1 which occurs constituitively in ADPKD was found to activate STAT3 via an Src-dependent process. This places STAT3 in the center of the abnormal signaling from polycystin to cyst growth in ADPKD.

60. Zhou J, Ouyang X, Schoeb TR, et al. Kidney injury accelerates cystogenesis via pathways modulated by heme oxygenase and complement. J Am Soc Nephrol 2012; 23:1161–1171.
61. Karihaloo A, Koraishy F, Huen SC, et al. Macrophages promote cyst growth in polycystic kidney disease. J Am Soc Nephrol 2011; 22:1809–1814.
62. Leonhard WN, van der Wal A, Novalic Z, et al. Curcumin inhibits cystogenesis by simultaneous interference of multiple signaling pathways: in vivo evidence from a Pkd1-deletion model. Am J Physiol Renal Physiol 2011; 300:F1193–F1202.
63. Takakura A, Nelson EA, Haque N, et al. Pyrimethamine inhibits adult polycystic kidney disease by modulating STAT signaling pathways. Hum Mol Genet 2011; 20:4143–4154.
64. Olsan EE, Mukherjee S, Wulkersdorfer B, et al. Signal transducer and activator of transcription-6 (STAT6) inhibition suppresses renal cyst growth in polycystic kidney disease. Proc Natl Acad Sci U S A 2011; 108:18067–18072.
65. Pang M, Ma L, Gong R, et al. A novel STAT3 inhibitor, S3I-201, attenuates renal interstitial fibroblast activation and interstitial fibrosis in obstructive nephropathy. Kidney international 2010; 78:257–268.
66. Liu N, He S, Ma L, et al. Blocking the class I histone deacetylase ameliorates renal fibrosis and inhibits renal fibroblast activation via modulating TGF-beta and EGFR signaling. PLoS One 2013; 8:e54001.
67. Koike K, Ueda S, Yamagishi S, et al. Protective role of JAK/STAT signaling against renal fibrosis in mice with unilateral ureteral obstruction. Clin Immunol 2014; 150:78–87.
68. Yukawa K, Kishino M, Goda M, et al. STAT6 deficiency inhibits tubulointerstitial fibrosis in obstructive nephropathy. Int J Mol Med 2005; 15:225–230.
69. He JC, Husain M, Sunamoto M, et al. Nef stimulates proliferation of glomerular podocytes through activation of Src-dependent Stat3 and MAPK1,2 pathways. J Clin Invest 2004; 114:643–651.
70. He JC, Lu TC, Fleet M, et al. Retinoic acid inhibits HIV-1-induced podocyte proliferation through the cAMP pathway. J Am Soc Nephrol 2007; 18:93–102.
71. Gu L, Dai Y, Xu J, et al. Deletion of podocyte STAT3 mitigates the entire spectrum of HIV-1-associated nephropathy. AIDS 2013; 27:1091–1098.
72. Correa-Costa M, Azevedo H, Amano MT, et al. Transcriptome analysis of renal ischemia/reperfusion injury and its modulation by ischemic preconditioning or hemin treatment. PLoS One 2012; 7:e49569.
73. Nechemia-Arbely Y, Barkan D, Pizov G, et al. IL-6/IL-6R axis plays a critical role in acute kidney injury. J Am Soc Nephrol 2008; 19:1106–1115.
74. Arany I, Reed DK, Grifoni SC, et al. A novel U-STAT3-dependent mechanism mediates the deleterious effects of chronic nicotine exposure on renal injury. Am J Physiol Renal Physiol 2012; 302:F722–F729.
75. Ogata K, Shimamura Y, Hamada K, et al. Upregulation of HNF-1beta during experimental acute kidney injury plays a crucial role in renal tubule regeneration. Am J Physiol Renal Physiol 2012; 303:F689–F699.
76▪. Susnik N, Sorensen-Zender I, Rong S, et al. Ablation of proximal tubular suppressor of cytokine signaling 3 enhances tubular cell cycling and modifies macrophage phenotype during acute kidney injury. Kidney Int 2014; 85:1357–1368.

In this study proximal tubular SOCS3 knockout mice maintained better kidney function when kidney injury was induced by aristolochic acid or ischemia/reperfusion confirming a protective role of STAT3 in AKI.

77. Yokota N, Burne-Taney M, Racusen L, Rabb H. Contrasting roles for STAT4 and STAT6 signal transduction pathways in murine renal ischemia-reperfusion injury. Am J Physiol Renal Physiol 2003; 285:F319–F325.

chronic kidney disease; Janus kinase; suppressors of cytokine signaling

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