PROTECTIVE ROLE OF MITOCHONDRIAL ALDEHYDE DEHYDROGENASE 2 (ALDH2) AGAINST BINGE ALCOHOL-INDUCED ACUTE KIDNEY INJURY THROUGH THE GUT-KIDNEY AXIS

Authors

• V Dulemba
• K Hitscherich
• S Sivashish
• A Dinerman
• F Lowery
• P Robbins
• J Hernandez
• S Krishna

Abstract

Introduction: Aldehyde dehydrogenase 2 (ALDH2) participates in the oxidative metabolism of alcohol. Studies have shown that Aldh2-knockout (KO) mice are susceptible to alcohol-mediated organ damage, but the mechanisms of binge alcohol induced-acute kidney injury (AKI) in Aldh2-KO mice are poorly understood. We hypothesized that exposure to three doses of alcohol may cause AKI due to increased gut barrier dysfunction (GBD) in Aldh2-KO mice compared to the corresponding WT mice.
Methods: WT and Aldh2-KO mice were exposed to three doses of alcohol (4 g/kg/dose via oral gavage) in 12-h intervals. Blood plasma, gut enterocytes, and kidney tissues were collected from each mouse at 1 hour and 24 hours after treatment. Serum creatinine levels, lipopolysaccharide (LPS) levels, expression of intestinal junction proteins (TJs/AJs), oxidative/nitrative stress markers (ROS/RNS), apoptosis-related proteins, and markers of kidney injury were measured.
Results: Aldh2-KO mice exposed to 3 doses of 4 g/kg ethanol showed elevated GBD, serum LPS, and serum creatinine, expression of kidney tissue proteins involved in apoptosis, ROS/RNS, and inflammation, gut enterocyte proteins involved in apoptosis and ROS/RNS, and less expression of TJs/AJs compared to the corresponding WT counterparts or dextrose-exposed Aldh2-KO, all suggesting that binge alcohol-mediated ROS/RNS may promote AKI through GBD and endotoxemia.
Conclusion: These mechanistic results are the first to report the critical role of GBD in the mechanism of alcohol-mediated AKI, exacerbated in an Aldh2-KO animal model. Furthermore, these results also suggest that ALDH2 is an important target for clinical intervention against alcohol-mediated tissue injury, including AKI.

Scientific Focus Area: Molecular Biology and Biochemistry

This page was last updated on Monday, September 25, 2023