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

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.

Acute high‐altitude hypoxia exposure causes neurological deficits via formaldehyde accumulation

“…Though the exact mechanisms needed further exploration, ALDH2 inhibition can directly promote ferroptosis in animal models 42 43 while increased in ALDH2 KO mice 44 …”

“…42 The concentrations of MDA (production of ferroptosis) and LPO were significantly decreased after ALDH2 activation, 43 while increased in ALDH2 KO mice. 44 Taken together, the disturbed FA metabolism and accumulated FA after acute hypobaric hypoxia exposure may evoke neuronal ferroptosis, and subsequent neurological dysfunction.…”

The Effects of Alda-1 Treatment on Renal and Intestinal Injuries After Cardiopulmonary Resuscitation in Pigs

“…Recently, one study demonstrated for the first time that Alda-1 treatment alleviated intestinal IR injury through the inhibition of oxidative stress, inflammatory response, and cell apoptosis ( 13 ). Two other studies demonstrated that ALDH2 overexpression mitigated IR-induced acute kidney injury by regulating cell autophagy via the beclin-1 pathway, and its activation by Alda-1 treatment alleviated renal IR injury in hypothermic machine perfusion through the Akt-mTOR autophagy signaling pathway ( 12 , 18 ).…”

“…In the CPR+Alda-1 group, a dose of 0.88 mg/kg of Alda-1 (Selleck Chemicals LLC., Houston, TX) was intravenously administered at 5 min after successful CPR. This dose of Alda-1 was chosen based on the previous studies and the principle of dose conversion ( 13 , 18 , 19 ), in which Alda-1 treatment was shown to effectively alleviate regional renal and intestinal IR injury in those small-animal models. In the other two groups, the same volume of vehicles was intravenously infused at the same time point.…”

Utility of SIFT-MS to evaluate volatile organic compounds in nephropathic patients’ breath

“…ALDH2 is involved in the oxidative production of ATP in the mitochondria, it reduces the reactive oxygen species (ROS) formation, attenuates the cellular response to oxidative stress, as evidenced by in vivo and in vitro studies, and it protects against ischemia–reperfusion injury in organs like heart, lung and gut 46 . In particular, ALDH2 protects renal tubular epithelial cells from oxidative stress and maintains the homeostasis of the kidney in the course of renal ischemia–reperfusion injury 47 . It has been hypothesized that the protective mechanisms of ALDH2 induces a reduced production of ROS by promoting autophagy, through the upregulation of the Beclin-1 pathway and the release of Bcl-2 47 .…”