Wang Zhiyu, Fu Zongjie, Wang Chongjian, Xu Jing, Ma Hongkun, Jiang Mengdi, Xu Tingting, Feng Xiaobei, Zhang Wen
Department of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine Shanghai 200025, China.
Department of Nephrology, Zhongshan Hospital, Fudan University Shanghai 200032, China.
Am J Transl Res. 2021 Sep 15;13(9):10014-10037. eCollection 2021.
To date, the treatment of acute kidney injury (AKI) remains a difficult problem for clinicians. In the present study, we assessed whether ZLN005, a novel peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) agonist, can protect against ischemic AKI in vivo and in vitro. Notably, ZLN005 treatment significantly alleviated Ischemia-reperfusion (I/R)-induced tubular injury and reversed the decrease in hypoxia-reoxygenation-induced cell viability by restoring PGC-1α expression in a dose-dependent manner. This beneficial effect of ZLN005 was associated with the preservation of mitochondrial fatty acid oxidation (MitoFAO) and the alleviation of oxidative stress. Cotreatment with etomoxir, a specific inhibitor of carnitine palmitoyltransferase-1α (CPT-1α) activity, or CPT-1α siRNA abrogated ZLN005-induced antistress responses by mitigating reactive oxygen species production and decreasing apoptosis under ischemia-hypoxia conditions by suppressing MitoFAO. Further studies revealed that activation of endoplasmic reticulum (ER) stress may be involved in the effect of CPT-1α inhibition observed in vivo and in vitro. Collectively, our results suggest that ZLN005 confers a protective effect on I/R-induced kidney injury by mitigating ER stress through the restoration of MitoFAO by targeting PGC-1α.
迄今为止，急性肾损伤（AKI）的治疗对临床医生来说仍然是一个难题。在本研究中，我们评估了新型过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）激动剂ZLN005在体内和体外是否能预防缺血性AKI。值得注意的是，ZLN005治疗通过以剂量依赖方式恢复PGC-1α表达，显著减轻了缺血再灌注（I/R）诱导的肾小管损伤，并逆转了缺氧复氧诱导的细胞活力下降。ZLN005的这种有益作用与线粒体脂肪酸氧化（MitoFAO）的保留和氧化应激的减轻有关。用肉碱棕榈酰转移酶-1α（CPT-1α）活性的特异性抑制剂依托莫西或CPT-1α siRNA共同处理，通过抑制MitoFAO减轻缺血缺氧条件下的活性氧产生并减少细胞凋亡，从而消除了ZLN005诱导的抗应激反应。进一步的研究表明，内质网（ER）应激的激活可能参与了体内和体外观察到的CPT-1α抑制作用。总的来说，我们的结果表明，ZLN005通过靶向PGC-1α恢复MitoFAO来减轻ER应激，从而对I/R诱导的肾损伤具有保护作用。
