Aldehyde dehydrogenase 2 protects against acute kidney injury by regulating autophagy via Beclin-1 pathway

• Published in: JCI insight Vol. 6; no. 15
• Main Authors: Xu, Tonghui, Guo, Jialin, Wei, Maozeng, Wang, Jiali, Yang, Kehui, Pan, Chang, Pang, Jiaojiao, Xue, Li, Yuan, Qiu-huan, Xue, Mengyang, Zhang, Jian, Sang, Wentao, Jiang, Tangxing, Chen, Yuguo, Xu, Feng
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 09.08.2021; American Society for Clinical investigation
• Subjects: Acute Kidney Injury - metabolism; Aldehyde Dehydrogenase, Mitochondrial - metabolism; Animals; Apoptosis - physiology; Autophagy - physiology; Beclin-1 - metabolism; Cell Survival; Cells, Cultured; Gene Expression Regulation; Humans; Kidney Tubules - metabolism; Kidney Tubules - pathology; Mice; Mitochondria - enzymology; Mitochondria - metabolism; Nephrology; Signal Transduction; Hypoxia; Autophagy; Nephrology
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.138183

The mitochondrial enzyme aldehyde dehydrogenase 2 (ALDH2) catalyzes the detoxification of acetaldehyde and endogenous lipid aldehydes. Approximately 40% of East Asians, accounting for 8% of the human population, carry the E504K mutation in ALDH2 that leads to accumulation of toxic reactive aldehydes and increases the risk for cardiovascular disease, cancer, and Alzheimer disease, among others. However, the role of ALDH2 in acute kidney injury (AKI) remains poorly defined and is therefore the subject of the present study using various cellular and organismal sources. In murine models, in which AKI was induced by either the contrast agent iohexol or renal ischemia/reperfusion, KO, activation/overexpression of ALDH2 were associated with increased and decreased renal injury, respectively. In murine renal tubular epithelial cells (RTECs), ALDH2 upregulated Beclin-1 expression, promoted autophagy activation, and eliminated ROS. In vivo and in vitro, both 3-MA and Beclin-1 siRNAs inhibited autophagy and abolished ALDH2-mediated renoprotection. In mice with iohexol-induced AKI, ALDH2 knockdown in RTECs using AAV-shRNA impaired autophagy activation and aggravated renal injury. In human renal proximal tubular epithelial HK-2 cells exposed to iohexol, ALDH2 activation potentiated autophagy and attenuated apoptosis. In mice with AKI induced by renal ischemia/reperfusion, ALDH2 overexpression or pretreatment regulated autophagy mitigating apoptosis of RTECs and renal injury. In summary, our data collectively substantiate a critical role of ALDH2 in AKI via autophagy activation involving the Beclin-1 pathway.