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

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

Cell reports (2020-10-01)
Xiao Wei, Zongshi Lu, Li Li, Hexuan Zhang, Fang Sun, Huan Ma, Lijuan Wang, Yingru Hu, Zhencheng Yan, Hongting Zheng, Gangyi Yang, Daoyan Liu, Martin Tepel, Peng Gao, Zhiming Zhu
ABSTRACT

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.

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