Inhibition of c-Src/p38 MAPK pathway ameliorates renal tubular epithelial cells apoptosis in db/db mice. (5th December 2015)

• Record Type: Journal Article
• Authors: Wu, Haijiang; Shi, Yonghong; Deng, Xinna; Su, Ye; Du, Chunyang; Wei, Jinying; Ren, Yunzhuo; Wu, Ming; Hou, Yanjuan; Duan, Huijun
• Is Part Of: Molecular and cellular endocrinology. Volume 417(2015)
• Page Start: 27
• Page End: 35
• Publication Date: 2015-12-05
• Subjects: Diabetic nephropathy -- db/db mice -- c-Src -- p38 MAPK -- Apoptosis; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2015.09.008
• Languages: English
• ISSNs: 0303-7207

Abstract

Abstract: Renal tubular epithelial cells (RTEC) apoptosis, which plays a key role in the pathogenesis and progression of diabetic nephropathy (DN), is believed to be contributive to the hyperglycemia-induced kidney failure, though the exact mechanisms remain elusive. In this study, we investigated how inhibition of c-Src/p38 MAPK pathway would affect RTEC apoptosis. The c-Src inhibitor PP2 i.p. administered every other day for 8 weeks to diabetic db/db mice significantly reduced their kidney weights, daily urinary volumes, blood glucose, blood urea nitrogen, serum creatinine, triglyceride and urine albumin excretion, whereas deactivation of c-Src and p38 MAPK were also observed, along with decreases in both Bax/Bcl-2 ratio and cleaved caspase-3 level in the kidneys. In vitro, exposure of HK-2 cells (a human RTEC line), to high glucose (HG) promoted phosphorylation of c-Src and p38 MAPK, and subsequently, as revealed by western blotting, TUNEL assay and flow cytometry, increased cell death, which can be inhibited by PP2. Especially, a specific p38 MAPK inhibitor, SB203580, that both attenuated HG-induced c-Src activation and abrogated the expression of PPARγ and CHOP, also reduced apoptosis. Taken together, PP2 inhibits c-Src and therefore reduces apoptosis in RTEC, which at least in part, is due to suppressed p38 MAPK activation in diabetic kidney. Highlights: Inhibition of c-Src activity improves metabolic parameters and prevents renal cell apoptosis in diabetic db/db mice. Inhibition of c-Src activity inhibits phosphorylation of c-Src and p38 MAPK in the kidneys of diabetic db/db mice. Inhibition of c-Src activity prevents HG-induced c-Src and p38 MAPK activation in HK-2 cells. Inhibition of p38 MAPK activity prevents HG-induced c-Src activation and expression of PPARγ and CHOP in HK-2 cells. Inhibition of c-Src or p38 MAPK activity prevents HG-induced apoptosis of HK-2 cells.