Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China.
Department of Endocrinology, Translational Research Key Laboratory for Diabetes, Xinqiao Hospital, Army Medical University, Chongqing 400037, China.
Cell Rep. 2020 Sep 29;32(13):108207. doi: 10.1016/j.celrep.2020.108207.
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.
糖尿病肾病（DN）是糖尿病的主要并发症，也是终末期肾衰竭的主要原因。临床研究表明，代谢手术可改善 DN，但具体机制尚不清楚。本研究报告称，Roux-en-Y 胃旁路术（RYGB）可显著阻断和逆转 DN，而不影响胰岛素信号通路。RYGB 手术的这种保护作用几乎被足细胞中 5'AMP 激活的蛋白激酶（AMPK）的抑制或敲除所阻断。此外，mRNA 微阵列数据显示，RYGB 手术明显降低了涉及烟酰胺腺嘌呤二核苷酸磷酸（NAPDH）合成的基因表达。手术后，血浆皮质酮水平降低，抑制了关键 NADPH 合成酶己糖-6-磷酸脱氢酶（H6PD）的表达。此外，通过敲低 H6PD 阻断 NAPDH 合成可通过激活足细胞中的 AMPK 来模拟 RYGB 手术的有益作用。因此，本研究表明，减少 NADPH 的产生对于 RYGB 手术引起的肾脏 AMPK 激活至关重要。
