title: Valsartan ameliorates podocyte loss in diabetic mice through the Notch pathway.
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.
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Biochemistry, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Yao
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China.
authors.forename: Shuxia
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China.
authors.forename: Qingjuan
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China.
authors.forename: Huijun
authors.initials: H
authors.lastname: Duan
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D003921:Diabetes Mellitus, Experimental; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000068756:Valsartan / Q000494:pharmacology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D015415:Biomarkers; D019253:Proto-Oncogene Proteins c-bcl-2; D051880:Receptors, Notch; D016159:Tumor Suppressor Protein p53; D000068756:Valsartan