#2272 HNF4a drives metabolic reprogramming in podocytes through ChREBP/SREBP-mediated pathway and promotes cell cycle progression

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Abstract Background and Aims Metabolic adaptation of podocytes plays an important role in diabetic kidney disease (DKD) progression. Recent studies have highlighted the importance of metabolic regulation in maintaining podocyte function under diabetic stress conditions. While hepatocyte nuclear factor 4 alpha (HNF4α) expression is elevated in diabetic podocytes and is known to regulate cellular metabolism in other tissues, its specific role and downstream metabolic effects in podocyte metabolism remain unclear. Understanding this mechanism is important, as podocytes require precise metabolic control to maintain their specialized functions. Method To investigate the metabolic regulatory role of HNF4α, we generated stable HNF4α-overexpressing mouse podocytes using lentiviral vectors. Metabolic changes were evaluated by measuring oxygen consumption rate (OCR), while the underlying mechanisms were assessed through Western blot analysis of metabolic enzymes and transcription factors. To determine the effect on cell growth, we performed cell cycle analysis using flow cytometry and proliferation assays. Results We found increased HNF4α expression in podocytes from db/db mice and DKD patients. To investigate the functional implications of this increased expression, we established HNF4α-overexpressing mouse podocytes. Western blot analysis showed upregulation of metabolic transcription factors, particularly ChREBP and SREBP, compared to control cells, along with increased protein levels of glycolytic enzymes, including PKM and HK2. Seahorse analysis demonstrated enhanced mitochondrial function in these cells, with increased basal OCR and maximal respiratory capacity compared to controls. Flow cytometry analysis revealed enhanced cell cycle progression in HNF4α-overexpressing podocytes, as evidenced by increased S phase population. Conclusion Our findings suggest that HNF4α influences podocyte metabolic pathways, potentially involving ChREBP/SREBP signaling, and affects cell cycle progression. These results provide insights into the role of HNF4α in podocyte metabolism, which may contribute to our understanding of podocyte regulation in DKD.

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