Intermedin mitigates chronic intermittent hypoxia-induced metabolic reprogramming in tubular epithelial cells and attenuates consequent kidney fibrosis through an AMPK-dependent suppression of HIF-1α.
TL;DR
It is demonstrated that IMD alleviates CIH-induced metabolic reprogramming in TECs and curbs kidney fibrosis via AMPK activation and consequent HIF-1α signaling, indicating that IMD suppresses HIF-1α through an AMPK-dependent mechanism.
Abstract
Obstructive sleep apnea-hypopnea syndrome (OSAHS) is an independent driver of chronic kidney disease (CKD). Its hallmark-chronic intermittent hypoxia (CIH)-induces oxidative stress, ultimately leading to kidney fibrosis. AMP-activated protein kinase (AMPK)-dependent suppression of hypoxia-inducible factor-1α (HIF-1α) regulates tubular epithelial cell (TEC) metabolic reprogramming during oxidative stress; its function under CIH remains undefined. Intermedin (IMD), an endogenous peptide with antioxidant effects via AMPK activation, has not been studied in CIH-induced fibrogenesis. We hypothesize IMD mitigates CIH-induced kidney fibrosis by re-programming TEC metabolism through the AMPK-HIF-1α pathway. We showed that CIH triggered kidney fibrosis in C57BL/6 J mice, concomitant with a marked induction of IMD and its receptor component. IMD deletion amplified CIH-induced kidney injury, with accelerated loss of kidney function, exaggerated fibrotic remodeling, rampant oxidative stress, amplified apoptotic cell death, and profound mitochondrial ultrastructural disorganization. Mechanistically, CIH induced metabolic reprogramming of TECs from fatty acid oxidation (FAO) toward glycolysis, IMD deficiency intensified this switch, whereas IMD supplementation restored FAO and suppressed glycolysis. Furthermore, enhancing FAO or inhibiting glycolysis partially rescued kidney fibrosis elicited by IMD deficiency, whereas FAO inhibition abolished IMD's renoprotection. At the molecular level, IMD activated AMPK and inhibited HIF-1α, thereby rebalancing FAO-glycolysis homeostasis and attenuating CIH-induced kidney fibrosis. Notably, AMPK inhibition abolished IMD-mediated HIF-1α suppression, whereas AMPK reactivation attenuated HIF-1α upregulation following IMD knockdown, indicating that IMD suppresses HIF-1α through an AMPK-dependent mechanism. Collectively, these findings demonstrate that IMD alleviates CIH-induced metabolic reprogramming in TECs and curbs kidney fibrosis via AMPK activation and consequent HIF-1α signaling.