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
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减少 NADPH 合成可通过恢复 1 型糖尿病大鼠的 AMPK 活性来对抗糖尿病肾病
DOI：
10.1016/j.celrep.2020.108207
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发表时间：
2020
期刊：
影响因子：
8.8
通讯作者：
Zhiming Zhu
中科院分区：
文献类型：
--
作者：
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
糖尿病肾病（diabetic nephropathy，DN）是糖尿病的主要并发症，也是导致终末期肾功能衰竭的主要原因。临床研究表明代谢手术可改善DN，但其机制尚不清楚。在这里，我们报告说，Roux-en-Y胃旁路（RYGB）手术显著阻断和逆转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活化蛋白激酶（AMPK）的抑制或敲除所阻断。此外，mRNA微阵列数据显示，RYGB手术明显降低了参与烟酰胺腺嘌呤二核苷酸磷酸（NAPDH）合成的基因表达。一个关键的NADPH合成酶，已糖-6-磷酸脱氢酶（H6 PD）的表达，被抑制的低血浆皮质酮水平手术后。此外，通过敲低H6 PD来阻断NAPDH合成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手术后肾AMPK的激活至关重要。
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.