Valsartan ameliorates podocyte loss in diabetic mice through the Notch pathway

Gao,Feng; Yao,Min; Cao,Yanping; Liu,Shuxia; Liu,Qingjuan; Duan,Huijun

doi:10.3892/ijmm.2016.2525

Valsartan ameliorates podocyte loss in diabetic mice through the Notch pathway

Authors:
- Feng Gao
- Min Yao
- Yanping Cao
- Shuxia Liu
- Qingjuan Liu
- Huijun Duan
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Affiliations: Department of Pathology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China, Department of Biochemistry, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
Published online on: March 11, 2016 https://doi.org/10.3892/ijmm.2016.2525
Pages: 1328-1336

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Abstract

The Notch pathway is known to be linked to diabetic nephropathy (DN); however, its underlying mechanism was poorly understood. In the present study, we examined the effect of Valsartan, an angiotensin II type 1 receptor antagonist, on the Notch pathway and podocyte loss in DN. Diabetes was induced in mice by an intraperitoneal injection of streptozotocin and and this was followed by treatment with Valsartan. Levels of blood glucose, kidney weight and body weight, as well as proteinuria were measured. Samples of the kidneys were also histologically examined. The relative levels of Jagged1, Notch1, Notch intracellular domain 1 (NICD1), Hes family BHLH transcription factor 1 (Hes1) and Hes-related family BHLH transcription factor with YRPW motif 1 expression (Hey1) in the glomeruli were determined by immunohistochemical analysis, western blot analysis and RT-qPCR. The B-Cell CLL/Lymphoma 2 (Bcl-2) and p53 pathways were examined by western blot analysis. Apoptosis and detachment of podocytes from the glomerular basement membrane were examined using a TUNEL assay, flow cytometric analysis and ELISA. The number of podocytes was quantified by measuring Wilms tumor-1 (WT-1) staining. We noted that the expression of Jagged1, Notch1, NICD1, Hes1 and Hey1 was increased in a time-dependent manner in the glomeruli of mice with streptozotocin (STZ)-induced diabetes. Moreover, in diabetic mice, Valsartan significantly reduced kidney weight and proteinuria, and mitigated the pathogenic processes in the kidneys. Valsartan also inhibited the activation of Notch, Bcl-2 and p53 pathways and ameliorated podocyte loss in the glomeruli of mice with STZ-induced diabetes. Taken together, these findings indicated that Valsartan exerted a beneficial effect on reducing podocyte loss, which is associated with inhibition of Notch pathway activation in the glomeruli of diabetic mice.

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