The effect of the interplay between PGC-1α and HIF-1α on preserving mitochondrial metabolism in diabetic kidney disease

Background Hypoxia-inducible factor-1 alpha (HIF-1α) plays a multifaceted role in energy metabolism by promoting glycolysis and inhibiting pyruvate kinase M2 (PKM2) activity. This study aimed to investigate the role of peroxisome proliferator-activated receptor- gamma coactivator-1 alpha (PGC-1α) in modulating HIF-1α-mediated regulation of mitochondrial metabolism in renal tubular epithelial cells (RTECs) under diabetic conditions.Methods Primary RTECs from the C57BL/6 mice were high glucose (HG)-stimulated, with or without transfection using the Ppargc1a plasmid (pPGC1α) or Ppargc1a small interfering RNA (siPGC1α). To evaluate whether PGC-1α regulates HIF-1α, chromatin immunoprecipitation (ChIP) and luciferase reporter assays were performed. In vivo, db/db mice received daily oral gavage of metformin or resveratrol for 12 weeks. This study examined tricarboxylic acid (TCA) cycle intermediates, PGC-1α, HIF-1α, PKM2, glycolysis, fatty acid oxidation (FAO), mitochondrial function, and morphology.Results HG-treated RTECs exhibited decreased Ppargc1a and Pkm2, increased Hif1a expression, a shift toward aberrant glycolysis, and impaired FAO. Ppargc1a overexpression reversed these changes, while silencing Ppargc1a exacerbated them. These changes were mitigated by silencing Hif1a. ChIP assay results indicated the binding of PGC-1α at the Hif1a promoter regulatory region. In an animal model of diabetic kidney disease, Ppargc1a activation with metformin and resveratrol partially recapitulated the in vitro findings, showing favorable metabolic effects.Conclusion PGC-1α deficiency under diabetic conditions led to TCA cycle intermediate accumulation, which enhanced HIF-1α activity and disrupted mitochondrial metabolism. PGC-1α negatively regulated HIF-1α expression, in part via promoter association, elucidating its regulatory role in mitochondrial metabolism.