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

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

  • Ren Fail. 2025 Dec;47(1):2568972. doi: 10.1080/0886022X.2025.2568972.
Xue Yang 1 2,  Qimeng Wang 1 2,  Huibin Nie 3,  Mingming Wang 1 2,  Yinghui Wang 1 2,  Shan Li 1 2,  Qingzhen Liu 1 2,  Gang Liu 1 2 4
Affiliations

Affiliations

  • 1 Nephrology Research Institute of Shandong University, Jinan, Shandong, China.
  • 2 Department of Nephrology, Multidisciplinary Innovation Center for Nephrology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • 3 Department of Nephrology, Chengdu First People's Hospital, Integrated TCM and Western Medicine Hospital Affiliated to Chengdu University of TCM, Chengdu, Sichuan, China.
  • 4 Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, China.
PMID: 41077842 DOI: 10.1080/0886022X.2025.2568972
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.

Keywords

Diabetic kidney disease (DKD); hypoxia-inducible factor 2α (HIF-2α); lipid metabolism; sphingosine-1-phosphate (S1P).

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