대한신장학회

논문분류	춘계학술대회 초록집
제목	The effect of PGC-1 on the interaction between HIF-1 and PKM2 to preserve mitochondrial metabolism in diabetic kidney disease
저자	Jee Young Lee
출판정보	2024; 2024(1):
키워드
초록	Objectives: Peroxisome proliferator-activated receptor (PPAR) gamma coactivator-1α (PGC-1α) is pivotal in mitochondrial biogenesis regulation, and its deficiency play a key role in kidney injury. Pyruvate kinase M2 (PKM2), acting as a glycolytic sensor, is implicated in mitochondrial dysfunction when defective. However, the potential interaction between PGC-1α and PKM2 remains unexplored. This study aimed to investigate the regulatory action of PGC-1α on PKM2 in renal tubular epithelial cells (RTECs) using mouse diabetic kidney disease (DKD) models. Methods: In an in vitro study, primary cultured RTECs from the C57BL/6 mice were exposed to high glucose (HG) with or without Ppargc1α plasmid or Ppargc1α small interfering RNA (siRNA). In an animal DKD study, db/db mice were treated with saline, metformin, or resveratrol daily via oral gavage for 12 weeks. We examined TCA cycle intermediates, hypoxia-inducible factor 1α (HIF-1α), PKM2 activity, and mitochondrial function and morphology. Results: HG-treated RTECs exhibited decreased PGC-1α expression, aberrant glycolysis, impaired fatty acid oxidation (FAO), and decreased mitochondrial function. We observed accumulation of succinate and fumarate, increased HIF-1α levels, and decreased PKM2 activity in these cells. These changes were restored by Ppargc1α overexpression, while exacerbated by silencing Ppargc1α. Notably, treatment with succinate in RTECs increased HIF-1α levels and decreased PKM2 activity, resulting in mitochondrial dysfunction. Moreover, chromatin immunoprecipitation assay revealed that PGC-1α directly bound to the regulatory region of the Hif1a promoter. The regulatory action of PGC-1α on HIF-1α was inhibited under HG exposure and potentiated by Ppargc1α overexpression and pharmacologic PGC-1α activation. In an animal DKD study, PGC-1α activation with metformin and resveratrol resulted in reduced accumulation of TCA intermediates, decreased HIF-1α levels, and improved PKM2 activity. Conclusions: This study demonstrates that PGC-1α enhances PKM2 activity via decreasing TCA cycle intermediate accumulation and suppressing HIF-1α activity. This dynamic interplay elucidates the mechanism underlying the observed improvement in mitochondrial function in DKD model.
원문(PDF)	PDF 원문보기

간행물 검색

대한신장학회 회원관리 규정