Hif1alpha ameliorates lipid-related injury of proximal tubular cell in diabetic nephropathy via transcriptional up-regulation of Annexin A1 to reduce non-esterified fatty acids.

Hypoxia-inducible factor 1 alpha (Hif1alpha) plays a critical role in lipid-related kidney injury in diabetic nephropathy (DN), but the exact mechanisms remain unclear. Notably, the sequestration of non-esterified fatty acids (NEFA), the main contributors to lipotoxicity, into lipid droplets (LDs) is a critical step in reducing lipid-related injury. For the first time, we observed a substantial elevation in NEFA levels and an exacerbation of lipid-related injury, along with a decrease in Annexin A1 (Anxa1) expression in the kidney tissue of high-fat diet/streptozotocin (HFD/STZ) treated mice with Hif1alpha knockout in proximal tubular cells (PTCs), compared to their Hif1alpha-intact counterparts (Hif1alphaCtrl). These observations were further confirmed by in vitro experiments. Additionally, the knockdown of Hif1alpha in PTCs partially worsened high glucose and palmitic acid (HGPA)-induced lipid-related injury, which could be counteracted by the overexpression of Anxa1. Furthermore, Anxa1 may facilitate the entry of excessive NEFA into LDs induced by HGPA, thereby reducing lipid-related injury. Mechanistically, Hif1alpha binds to the hypoxia-responsive element (HRE) motif in the Anxa1 promoter and enhances transcription of Anxa1 under HGPA conditions. Collectively, our findings suggest that Hif1alpha upregulates Anxa1 expression at the transcriptional level, promoting NEFA incorporation into LDs and ultimately reducing renal lipid-related injury in DN.