RRC ID 66159
Author Xu T, Guo J, Wei M, Wang J, Yang K, Pan C, Pang J, Xue L, Yuan Q, Xue M, Zhang J, Sang W, Jiang T, Chen Y, Xu F.
Title Aldehyde dehydrogenase 2 protects against acute kidney injury by regulating autophagy via the Beclin-1 pathway.
Journal JCI Insight
Abstract The mitochondrial enzyme acetaldehyde 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 (CVD), cancer and Alzheimer's, among other diseases. 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, knockout and activation/overexpression of ALDH2 was 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 reactive oxygen species (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 ischemia/reperfusion, ALDH2 overexpression or pretreatment regulated autophagy mitigating apoptosis of RTECs and renal injury. Our data collectively substantiate a critical role of ALDH2 in AKI via autophagy activation involving the Beclin-1 pathway.
Volume 6(15)
Published 2021-8-9
DOI 10.1172/jci.insight.138183
PII e138183
PMID 34228649
PMC PMC8410052
MeSH 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 Signal Transduction
IF 6.205
Mice RBRC05808