Blockage of JAK/STAT signalling attenuates renal ischaemia-reperfusion injury in rats

Yang, Niansheng; Luo, Moulun; Li, Rong; Huang, Yuefang; Rui, Zhang; Wu, Qin; Wang, Fang; Li, Youji; Yu, Xueqing

doi:10.1093/ndt/gfm509

Cited by 99 publications

(90 citation statements)

References 40 publications

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“…However, the localization of JAK/STAT activation is not known. 24 In this study, we showed that activation of pSTAT3 was strongly detected in the kidneys after I/R ( Figure 2E). Also, in situ immunohistochemistry staining of pSTAT3 showed that activation of STAT3 was observed in all types of the tubular epithelial cells except the proximal tubular epithelial cells, which was in contrast to the IL-22-mediated specific activation of STAT3 in the proximal tubular epithelial cells ( Figure 2F).…”

Section: Il-22 Treatment Ameliorates Renal I/r Injury By Activating Ssupporting

confidence: 56%

IL-22 Ameliorates Renal Ischemia-Reperfusion Injury by Targeting Proximal Tubule Epithelium

Feng

Wang

et al. 2014

Journal of the American Society of Nephrology

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IL-22 is an epithelial cell survival cytokine that is currently under development for the treatment of acute liver damage. Here, we used a mouse model of renal ischemia/reperfusion (I/R) injury to investigate whether IL-22 has therapeutic potential for the treatment of AKI. The action of IL-22 is mediated by binding to IL-22R1 and leads to STAT3 activation. Under physiologic conditions, renal expression of IL-22R1 was detected only in the brush border of the renal proximal tubular epithelial cells (RPTECs). Renal I/R elevated serum IL-22 levels slightly but did not induce STAT3 phosphorylation in RPTECs. IL-22-deficient mice had slightly increased I/R-induced injury compared with wild-type mice. In contrast, treatment with IL-22 or overexpression of IL-22 by either gene targeting (IL-22 transgenic mice) or administration of adenovirus expressing IL-22 increased STAT3 phosphorylation in RPTECs, ameliorated I/R-induced renal inflammation and tubular cell injury, and preserved renal functions. Overexpression of IL-22 increased the phosphorylation of STAT3 and Akt, upregulated antiapoptotic genes (e.g., Bcl-2), and downregulated proapoptotic genes (e.g., Bad) in the kidneys of mice subjected to I/R. Notably, phosphorylation of Akt increased and expression of Bad decreased in proximal tubular cells under these conditions. Furthermore, compared with wild-type mice, IL-22 transgenic mice had increased survival rates, whereas IL-22-deficient mice had reduced survival rates after I/R injury. In summary, renal expression of IL-22R1 is restricted to RPTECs, and treatment with IL-22 protects against renal I/R injury by activating STAT3 and AKT, suggesting that IL-22 has therapeutic potential for the treatment of AKI.

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Section: Il-22 Treatment Ameliorates Renal I/r Injury By Activating Ssupporting

confidence: 56%

IL-22 Ameliorates Renal Ischemia-Reperfusion Injury by Targeting Proximal Tubule Epithelium

Feng

Wang

et al. 2014

Journal of the American Society of Nephrology

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“…p53-mediated induction of DUSP5 may, therefore, block extracellular signal-regulated kinase signaling and its role in ischemic AKI. 42 Txnip is a modulator of cellular redox state that contributes to cell apoptosis. 43 In mice, knockout of Txnip impairs mitochondrial function but protects myocardium from ischemiareperfusion injury.…”

Section: Discussionmentioning

confidence: 99%

Tubular p53 Regulates Multiple Genes to Mediate AKI

Zhang

Liu

Wei

et al. 2014

Journal of the American Society of Nephrology

142

163

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A pathogenic role of p53 in AKI was suggested a decade ago but remains controversial. Indeed, recent work indicates that inhibition of p53 protects against ischemic AKI in rats but exacerbates AKI in mice. One intriguing possibility is that p53 has cell type-specific roles in AKI. To determine the role of tubular p53, we generated two conditional gene knockout mouse models, in which p53 is specifically ablated from proximal tubules or other tubular segments, including distal tubules, loops of Henle, and medullary collecting ducts. Proximal tubule p53 knockout (PT-p53-KO) mice were resistant to ischemic and cisplatin nephrotoxic AKI, which was indicated by the analysis of renal function, histology, apoptosis, and inflammation. However, other tubular p53 knockout (OT-p53-KO) mice were sensitive to AKI. Mechanistically, AKI associated with the upregulation of several known p53 target genes, including Bax, p53-upregulated modulator of apoptosis-a, p21, and Siva, and this association was attenuated in PT-p53-KO mice. In global expression analysis, ischemic AKI induced 371 genes in wild-type kidney cortical tissues, but the induction of 31 of these genes was abrogated in PT-p53-KO tissues. These 31 genes included regulators of cell death, metabolism, signal transduction, oxidative stress, and mitochondria. These results suggest that p53 in proximal tubular cells promotes AKI, whereas p53 in other tubular cells does not.

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“…Yang et al (69) reported that JAK2/STAT1/3 signals were activated in the kidneys after ischemia-reperfusion (I/R) and that blockage of JAK2 by AG490 attenuates I/R-induced These studies suggest that STAT3 may be an important molecule in the mechanical signaling of renal tubular cells during obstructive nephropathy. In this report, it is demonstrated that STAT3 is required for TGF-␤1 and fibronectin expression by immortalized tubular epithelial cells exposed to cyclic mechanical stretch.…”

Section: Discussionmentioning

confidence: 99%

Cyclic stretch-induced TGF-β1 and fibronectin expression is mediated by β1-integrin through c-Src- and STAT3-dependent pathways in renal epithelial cells

Hamzeh

Sridhara

Alexander

2015

American Journal of Physiology-Renal Physiology

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Blockage of JAK/STAT signalling attenuates renal ischaemia-reperfusion injury in rats

Abstract: This study demonstrated the involvement of JAK/STAT signalling in the pathogenesis of renal I/R injury, suggesting that JAK/STAT pathway may serve as a potential target for early intervention in ischaemic acute renal failure.

Cited by 99 publications

References 40 publications

IL-22 Ameliorates Renal Ischemia-Reperfusion Injury by Targeting Proximal Tubule Epithelium

IL-22 Ameliorates Renal Ischemia-Reperfusion Injury by Targeting Proximal Tubule Epithelium

Tubular p53 Regulates Multiple Genes to Mediate AKI

Cyclic stretch-induced TGF-β1 and fibronectin expression is mediated by β1-integrin through c-Src- and STAT3-dependent pathways in renal epithelial cells

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