Remnant Kidney Impairments And Metabolic Disorders Induced By Rennin-angiotensin System

Objective: Renal renin-angiotensin system(RAS) and the ultrasensitive energy sensor AMP-activated protein kinase(AMPK) has been implicated in normal and aberrant states of kidney and lipid, glucose metabolisms, but interaction between RAS and AMPK remains unknown. Here we report the interaction of RAS and AMPK in rats with renal disease and dysmetabolism by uninephrectomized(UNX) model. Methods: 112 rats were stratified into four groups: sham, UNX, UNX treated with angiotensin converting enzyme inhibitor(ACEI) Lisinopril or angiotensin receptor blocker(ARB) Losartan. At 3, 6, 8 and 10 months post-operation, renal functions reflected by fasting serum urea, creatinine, and albumin while fasting serum lipids including total cholesterol, triglyceride, high density lipoprotein-cholesterol(HDL-C) and low density lipoprotein-cholesterol(LDL-C) were detected by biochemical methods among the four groups. At 10 months, microscopic examinations of four group rats were performed to assess kidney. Meanwhile, expressions of AMPK in renal cortex were examined by immunofluorescence, and expressions of AMPK and acetyl-CoA carboxylase(ACC) by immunihistochemistry and western blot. Results: Compared with sham rats, UNX rats demonstrated progressive glomerulosclerosis, tubular atrophy with cast and chronic inflammatory infiltration, in parallel to elevated serum urea, creatinine and reduced serum albumin. UNX rats also showed hyperlipidemia and hyperglycemia, reflected by high levels of total cholesterol, triglyceride, HDL-C, LDL-C and fasting blood glucose. At 10 months, reduced AMPK expression and over-expression of ACC were detected by immunofluorescence, immunohistochemistry and western blot. Conclusions: UNX triggered RAS activation of renal cortex, kidney damages and dysmetabolism of lipid and glucose in rats, and RAS inhibitors ameliorated all of the abnormalities including interruption of AMPK signaling pathway. Considering of the direct regulations of AMPK and ACC on kidney and metabolisms, therefore, we hypothesize that RAS activation in UNX rats may induce the renal dysfunction and metabolic disorders via inhibiting AMPK signaling pathway.