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Involvement of spliced X-box binding protein 1 in renal fibrosis induced by unilateral ureteral obstruction in mice

SHAO De-Cui, MIAO Nai-Jun, LI Jia-Jia

The Cell Electrophysiology Laboratory, Wannan Medical College, Wuhu 241002, China； Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China； Department of Pathophysiology, The First Affiliated Hospital of Wannan Medical College, Wuhu 241002, China

Abstract

Endoplasmic reticulum (ER) stress is involved in the process of kidney fibrosis. Spliced X-box binding protein 1 (XBP1S) is the key mediator of ER stress while its role in fibrosis is still poorly understood. This study was aimed to investigate the role of XBP1S in renal fibrosis and evaluate whether valsartan could alleviate fibrosis through XBP1S. Renal interstitial fibrosis was induced by unilateral ureteral obstruction (UUO) in C57BL/6 mice, and UUO mice were daily administered with valsartan (20 mg/kg) through oral gavage. After 7 days of UUO, at euthanasia, left kidney was collected to examine the histological alteration by using haematoxylin-eosin staining, Masson’s trichrome staining, Sirius red staining and immunohistochemistry. Western blot was used to assess XBP1S, targets of XBP1S, fibronectin, α-SMA, BAX and BCL2 protein levels. Real-time polymerase chain reaction was performed to assess NADPH oxidase subunits p47-phox and p67-phox mRNA levels. The results showed that XBP1S expression was decreased by about 70% in the UUO mice compared with that in sham mice (P < 0.01), which was reversed by valsartan administration (P < 0.05). Meanwhile, UUO-induced renal interstitial fibrosis was attenuated by valsartan treatment. In addition, the protein levels of fibronectin and α-SMA were upregulated by UUO induction (P < 0.01), and valsartan administration inhibited the protein levels of fibronectin and α-SMA in UUO mice (P < 0.05). Western blot analysis showed that the ratio of BAX to BCL2 protein level was increased in UUO model compared with that in sham mice, and the increment also was diminished by valsartan treatment (P < 0.05). Finally, UUO-induced mRNA levels of p47-phox and p67-phox were significantly attenuated by valsartan administration (P < 0.05). These results showed that valsartan at least partly restores renal interstitial fibrosis by enhancing XBP1S activation through inhibiting oxidative stress and apoptosis in the UUO mice. These results suggest that XBP1S could be a potential therapeutic target for kidney fibrosis.

Key words: endoplasmic reticulum stress; fibrosis; spliced X-box binding protein 1; oxidative stress

Received: 2015-11-06　　Accepted: 2016-02-23

Corresponding author: 邵德翠　　E-mail: shaodecui@sina.com

Citing This Article：

SHAO De-Cui, MIAO Nai-Jun, LI Jia-Jia. Involvement of spliced X-box binding protein 1 in renal fibrosis induced by unilateral ureteral obstruction in mice. Acta Physiol Sin 2016; 68 (2): 157-164 (in Chinese with English abstract).