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

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.