Reducing NADPH Synthesis Counteracts Diabetic Nephropathy through Restoration of AMPK Activity in Type 1 Diabetic Rats

Diabetic nephropathy (DN) is a major complication of diabetes mellitus and a primary cause of end-stage renal failure. Clinical studies indicate that metabolic surgery improves DN; however, the mechanism remains unclear. Here, we report that Roux-en-Y Gastric Bypass (RYGB) surgery significantly blocked and reversed DN without affecting the insulin signaling pathway. This protective role of RYGB surgery is almost blocked by either inhibition or knockout of 5′AMP-activated protein kinase (AMPK) in podocytes. Furthermore, mRNA microarray data reveal that RYGB surgery obviously reduced the gene expression involved in nicotinamide adenine dinucleotide phosphate (NAPDH) synthesis. The expression of a key NADPH synthase, hexose-6-phosphate dehydrogenase (H6PD), was inhibited by the low plasma corticosterone level after surgery. In addition, blocking NAPDH synthesis by knocking down H6PD mimicked the beneficial role of RYGB surgery through activation of AMPK in podocytes. Therefore, this study demonstrates that reducing NADPH production is critical for renal AMPK activation in response to RYGB surgery. [Display omitted] •RYGB surgery significantly improves diabetic nephropathy in type 1 diabetes•RYGB ameliorates mitochondrial dysfunction in podocytes by activating AMPK•RYGB surgery restores AMPK activity by reducing NAPDH synthesis•Elevated NAPDH level competes with AMP binding on AMPK in diabetic rats Wei et al. reveal that an elevated NAPDH level is the main reason for AMPK reduction in podocytes of type 1 diabetic rats by competing with AMP binding on AMPK. RYGB surgery restores AMPK activity and improves diabetic nephropathy by reducing NADPH synthesis.