Abstract
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.
Highlights
Acute kidney injury (AKI) has been recognized as a major public health problem affecting millions of patients worldwide and leading to decreased survival [1]
We identified a potentially novel mechanism whereby aldehyde dehydrogenase 2 (ALDH2) limits ROS levels by promoting autophagy via Beclin-1 upregulation and release from Bcl-2 sequestration contributing to protection of renal tubular epithelial cells (RTECs) from oxidative stress and maintenance of kidney hemostasis during Contrast-induced AKI (CI-AKI) and ischemia/reperfusion injury (IRI)
The renal cortex from ALDH2-KO CI-AKI mice had a higher level of MDA and a lower level of SOD than that of WT CI-AKI mice (Figure 1A)
Summary
Acute kidney injury (AKI) has been recognized as a major public health problem affecting millions of patients worldwide and leading to decreased survival [1]. AKI occurs in patients with renal hypoperfusion, cardiovascular disease, sepsis, major surgery, radiocontrast exposure, and pharmacological treatments [3,4,5,6,7,8]. Development of AKI in the hospital is associated with an extended length of stay, accelerated onset of end-stage renal disease, increased costs, and increased mortality [12]. Despite recent insights into the causes and underlying mechanisms, no interventions beyond supportive treatment have been developed to improve outcomes of established AKI [16, 17]
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