Hypoxia-inducible factor 2α overexpression in podocytes ameliorates lipid metabolism disorders in diabetic kidney disease by inhibiting S1P.

IF 3 3区医学 Q1 UROLOGY & NEPHROLOGY

Renal Failure Pub Date : 2025-12-01 Epub Date: 2025-10-12 DOI:10.1080/0886022X.2025.2568972

Xue Yang, Qimeng Wang, Huibin Nie, Mingming Wang, Yinghui Wang, Shan Li, Qingzhen Liu, Gang Liu

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Abstract

Background and aims: Lipid accumulation in podocytes is a major driver of diabetic kidney disease (DKD). Hypoxia-inducible factor 2α (HIF-2α) plays an important role in regulating metabolism. The function of HIF-2α in lipid metabolism in podocytes and the progression of DKD remain unclear.

Methods: We investigated the effects of HIF-2α on podocyte damage and lipid metabolism using immunofluorescence, flow cytometry, ELISA, and Western blotting. In order to characterize the regulatory effects of HIF-2α, we also used ChIP and dual-luciferase reporter assays to investigate the role of sphingosine kinase 1 (SPHK1), a crucial enzyme in sphingosine-1-phosphate (S1P) synthesis. In vivo, the effect of HIF-2α on lipid metabolism disorders in db/db mice was investigated using the HIF-2α inhibitor PT-2385.

Results: Our results revealed that HIF-2α overexpression improved lipid metabolism in DKD by enhancing cholesterol efflux via reduced S1P synthesis in podocytes by 25.69%. Inhibition of HIF-2α expression in the mouse model of diabetes exacerbated podocyte damage and proteinuria. Inhibition of SPHK1 expression rescued HIF-2α knockdown-mediated lipid disorders in podocytes. HIF-2α inhibited the transcription of SPHK1 by binding to the promoter region of SPHK1 and reduced S1P synthesis. Furthermore, we found that FG-4592, a HIF prolyl hydroxylase inhibitor, reduced the total cholesterol level in DKD by activating HIF-2α, thereby protecting against DKD.

Conclusion: HIF-2α ameliorated lipid metabolism disorders and podocyte damage in DKD by downregulating S1P, providing a novel insight for HIF-2α against DKD.

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足细胞中缺氧诱导因子2α的过表达通过抑制S1P改善糖尿病肾病的脂质代谢紊乱。

背景和目的：足细胞脂质积累是糖尿病肾病（DKD）的主要驱动因素。缺氧诱导因子2α (HIF-2α)在调节机体代谢中起着重要作用。HIF-2α在足细胞脂质代谢和DKD进展中的作用尚不清楚。方法：采用免疫荧光、流式细胞术、ELISA、Western blotting等方法研究HIF-2α对足细胞损伤及脂质代谢的影响。为了表征HIF-2α的调控作用，我们还使用ChIP和双荧光素酶报告基因检测来研究鞘氨醇激酶1 （SPHK1）的作用，SPHK1是鞘氨醇-1-磷酸（S1P）合成中的关键酶。在体内，利用HIF-2α抑制剂PT-2385研究了HIF-2α对db/db小鼠脂质代谢紊乱的影响。结果：我们的研究结果显示，HIF-2α过表达通过减少足细胞中S1P合成而增加胆固醇外排，从而改善DKD的脂质代谢，减少了25.69%。抑制HIF-2α在糖尿病小鼠模型中的表达可加重足细胞损伤和蛋白尿。抑制SPHK1表达可挽救HIF-2α敲低介导的足细胞脂质紊乱。HIF-2α通过结合SPHK1的启动子区域抑制SPHK1的转录，减少S1P的合成。此外，我们发现FG-4592，一种HIF脯氨酰羟化酶抑制剂，通过激活HIF-2α降低DKD中的总胆固醇水平，从而保护DKD。结论：HIF-2α通过下调S1P改善DKD的脂质代谢紊乱和足细胞损伤，为HIF-2α抗DKD提供了新的认识。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Renal Failure 医学-泌尿学与肾脏学

CiteScore

3.90

自引率

13.30%

发文量

374

审稿时长

1 months

期刊介绍： Renal Failure primarily concentrates on acute renal injury and its consequence, but also addresses advances in the fields of chronic renal failure, hypertension, and renal transplantation. Bringing together both clinical and experimental aspects of renal failure, this publication presents timely, practical information on pathology and pathophysiology of acute renal failure; nephrotoxicity of drugs and other substances; prevention, treatment, and therapy of renal failure; renal failure in association with transplantation, hypertension, and diabetes mellitus.