Dexmedetomidine Attenuates Ferroptosis-Mediated Renal Ischemia/Reperfusion Injury and Inflammation by Inhibiting ACSL4 via α2-AR

Wen-Hui Tao; Xi-Sheng Shan; Jia-Xin Zhang; Hua-Yue Liu; Bi-Ying Wang; Xiang Wei; Mian Zhang; Ke Peng; Jun Ding; Shang-Xian Xu; Lin-Gui Li; Jun-Kai Hu; Xiao-Wen Meng; Fu-Hai Ji

doi:10.3389/fphar.2022.782466

Dexmedetomidine Attenuates Ferroptosis-Mediated Renal Ischemia/Reperfusion Injury and Inflammation by Inhibiting ACSL4 via α2-AR

Front Pharmacol. 2022 Jun 14:13:782466. doi: 10.3389/fphar.2022.782466. eCollection 2022.

Authors

Wen-Hui Tao^{1

2}, Xi-Sheng Shan^{1

2}, Jia-Xin Zhang¹, Hua-Yue Liu^{1

2}, Bi-Ying Wang¹, Xiang Wei¹, Mian Zhang^{1

2}, Ke Peng^{1

2}, Jun Ding¹, Shang-Xian Xu¹, Lin-Gui Li^{1

2}, Jun-Kai Hu^{1

2}, Xiao-Wen Meng^{1

2}, Fu-Hai Ji^{1

2}

Affiliations

¹ Department of Anesthesiology, First Affiliated Hospital of Soochow University, Soochow, China.
² Institute of Anesthesiology, Soochow University, Soochow, China.

Abstract

Ischemia-reperfusion (I/R) injury is a serious clinical pathology associated with acute kidney injury (AKI). Ferroptosis is non-apoptotic cell death that is known to contribute to renal I/R injury. Dexmedetomidine (Dex) has been shown to exert anti-inflammatory and organ protective effects. This study aimed to investigate the detailed molecular mechanism of Dex protects kidneys against I/R injury through inhibiting ferroptosis. We established the I/R-induced renal injury model in mice, and OGD/R induced HEK293T cells damage in vitro. RNA-seq analysis was performed for identifying the potential therapeutic targets. RNA-seq analysis for differentially expressed genes (DEGs) reported Acyl-CoA synthetase long-chain family member 4 (ACSL4) related to ferroptosis and inflammation in I/R mice renal, which was validated in rodent renal. Liproxstatin-1, the specific small-molecule inhibitor of ferroptosis, significantly attenuated ferroptosis-mediated renal I/R injury with decreased LPO, MDA, and LDH levels, and increased GSH level. Inhibiting the activity of ACSL4 by the Rosiglitazone (ROSI) resulted in the decreased ferroptosis and inflammation, as well as reduced renal tissue damage, with decreasing LPO, MDA and LDH level, increasing GSH level, reducing COX2 and increasing GPx4 protein expression, and suppressing the TNF-α mRNA and IL-6 mRNA levels. Dex as a α2-adrenergic receptor (α2-AR) agonist performed renal protective effects against I/R-induced injury. Our results also revealed that Dex administration mitigated tissue damage, inhibited ferroptosis, and downregulated inflammation response following renal I/R injury, which were associated with the suppression of ACSL4. In addition, ACSL4 overexpression abolishes Dex-mediated protective effects on OGD/R induced ferroptosis and inflammation in HEK293T cells, and promotion of ACSL4 expression by α2-AR inhibitor significantly reversed the effects on the protective role of Dex. This present study indicated that the Dex attenuates ferroptosis-mediated renal I/R injury and inflammation by inhibiting ACSL4 via α2-AR.

Keywords: ACSL4; Dexmedetomidine; Inflammation; Renal ischemia/reperfusion injury; ferroptosis; α2-adrenergic receptor.