RAS Blockade Inhibits Bcl‐2 Modifying Factor (Bmf) Expression and Prevents Hypertension and Tubular Apoptosis in Diabetic Akita Mouse Kidneys

Abstract

BackgroundWe reported that pro‐apoptotic protein Bmf is highly expressed in diabetic mouse renal proximal tubular cells (RPTCs) and induces RPTC apoptosis in vitro (Diabetes 2012). The regulation of Bmf expression in RPTCs, however, is not well understood. We investigated whether renin‐angiotensin system (RAS) blockade could prevent Bmf expression, hypertension and RPTC apoptosis in Akita mice (a model of type 1 diabetes) in vivo and in vitro.MethodsAdult male Akita mice (11 weeks) were treated ± RAS blockers (losartan, 30 mg.Kg−1.day−1 and perindopril, 4 mg.Kg− 1.day−1 in drinking water) until 16 weeks. Controls were untreated non‐Akita littermates. Plasma glucose, systolic blood pressure (SBP) and albuminuria were monitored weekly. Kidneys were processed for histology and apoptosis studies (TUNEL assay). RPTC gene and protein expression were quantified by real time‐qPCR and Western blotting, respectively. We also examined the effect of angiotensin II (Ang II) on Bmf gene expression in cultured rat immortalized RPTCs.ResultsAkita mice developed hyperglycemia and significantly higher SBPs, kidney/body weight ratios and albuminuria, cf. to non‐Akita littermates. Kidneys from Akita mice displayed renal hypertrophy and tubular apoptosis cf. to non‐Akita littermates. Increased expression of Agt, Bmf and active caspase‐3 were evident in RPTCs of Akita mice. Treatment with RAS blockers inhibited Agt and Bmf expression, prevented hypertension and albuminuria and attenuated tubular apoptosis in Akita mice. Finally, Ang II stimulated Bmf mRNA expression in RPTCs and its effect was abolished in the presence of losartan.ConclusionAng II up‐regulates Bmf expression and RAS blockade effectively inhibits Bmf expression and prevents hypertension and tubular apoptosis in diabetic kidneys.Supported by Canadian Institutes of Health Research.