1. Academic Validation
  2. ZLN005 protects against ischemia-reperfusion-induced kidney injury by mitigating oxidative stress through the restoration of mitochondrial fatty acid oxidation

ZLN005 protects against ischemia-reperfusion-induced kidney injury by mitigating oxidative stress through the restoration of mitochondrial fatty acid oxidation

  • Am J Transl Res. 2021 Sep 15;13(9):10014-10037.
Zhiyu Wang 1 Zongjie Fu 2 Chongjian Wang 1 Jing Xu 1 Hongkun Ma 1 Mengdi Jiang 1 Tingting Xu 1 Xiaobei Feng 1 Wen Zhang 1
Affiliations

Affiliations

  • 1 Department of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine Shanghai 200025, China.
  • 2 Department of Nephrology, Zhongshan Hospital, Fudan University Shanghai 200032, China.
PMID: 34650679
Abstract

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.

Keywords

Acute kidney injury; ZLN005; apoptosis; carnitine palmitoyl transferase-1α; oxidative stress; peroxisome proliferator-activated receptor-γ coactivator-1α.

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