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

<b>Background and aims: </b>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. <b>Methods: </b>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. <i>In vivo</i>, the effect of HIF-2α on lipid metabolism disorders in db/db mice was investigated using the HIF-2α inhibitor PT-2385. <b>Results: </b>Our results revealed that HIF-2α overexpression improved lipid metabolism in DKD by enhancing cholesterol efflux <i>via</i> 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. <b>Conclusion: </b>HIF-2α ameliorated lipid metabolism disorders and podocyte damage in DKD by downregulating S1P, providing a novel insight for HIF-2α against DKD.