中介素通过AMPK依赖性抑制HIF-1α减轻慢性间歇性缺氧诱导的肾小管上皮细胞代谢重编程并缓解随后的肾纤维化

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中文摘要

阻塞性睡眠呼吸暂停低通气综合征（OSAHS）是慢性肾脏病（CKD）的独立驱动因素。其标志性特征——慢性间歇性缺氧（CIH）——诱导氧化应激，最终导致肾纤维化。AMP活化蛋白激酶（AMPK）依赖性抑制缺氧诱导因子-1α（HIF-1α）调控氧化应激期间肾小管上皮细胞（TEC）的代谢重编程；其在CIH下的功能尚未明确。中介素（IMD）是一种通过AMPK激活发挥抗氧化作用的内源性肽，尚未在CIH诱导的纤维化中进行研究。我们假设IMD通过AMPK-HIF-1α通路重编程TEC代谢，从而减轻CIH诱导的肾纤维化。我们发现，CIH在C57BL/6J小鼠中引发肾纤维化，同时显著诱导IMD及其受体组分。IMD缺失加剧了CIH诱导的肾损伤，表现为肾功能加速丧失、纤维化重塑加重、氧化应激猖獗、凋亡细胞死亡增加以及线粒体超微结构严重紊乱。机制上，CIH诱导TEC从脂肪酸氧化（FAO）向糖酵解的代谢重编程，IMD缺乏加剧了这一转变，而IMD补充则恢复FAO并抑制糖酵解。此外，增强FAO或抑制糖酵解可部分挽救IMD缺乏引起的肾纤维化，而抑制FAO则消除了IMD的肾脏保护作用。在分子水平上，IMD激活AMPK并抑制HIF-1α，从而重新平衡FAO-糖酵解稳态并减轻CIH诱导的肾纤维化。值得注意的是，抑制AMPK消除了IMD介导的HIF-1α抑制，而AMPK再激活减弱了IMD敲低后的HIF-1α上调，表明IMD通过AMPK依赖性机制抑制HIF-1α。总之，这些发现表明IMD通过AMPK激活及随后的HIF-1α信号通路，减轻CIH诱导的TEC代谢重编程并抑制肾纤维化。

英文摘要

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.