Advertisement

ResearchIn-Press PreviewMetabolismNephrology Open Access | 10.1172/jci.insight.179871

Aldehyde dehydrogenase 2 preserves kidney function by countering acrolein-induced metabolic and mitochondrial dysfunction

Szu-yuan Li,1 Ming-Tsun Tsai,1 Yu-Ming Kuo,3 Hui-Min Yang,3 Zhen-Jie Tong,3 Hsiao-Wei Cheng,3 Chih-Ching Lin,1 and Hsiang-Tsui Wang3

1Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Tapei, Taiwan

2Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

3Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

Find articles by Li, S. in: JCI | PubMed | Google Scholar

1Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Tapei, Taiwan

2Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

3Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

Find articles by Tsai, M. in: JCI | PubMed | Google Scholar

1Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Tapei, Taiwan

2Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

3Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

Find articles by Kuo, Y. in: JCI | PubMed | Google Scholar

1Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Tapei, Taiwan

2Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

3Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

Find articles by Yang, H. in: JCI | PubMed | Google Scholar

1Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Tapei, Taiwan

2Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

3Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

Find articles by Tong, Z. in: JCI | PubMed | Google Scholar

1Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Tapei, Taiwan

2Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

3Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

Find articles by Cheng, H. in: JCI | PubMed | Google Scholar

1Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Tapei, Taiwan

2Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

3Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

Find articles by Lin, C. in: JCI | PubMed | Google Scholar

1Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Tapei, Taiwan

2Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

3Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

Find articles by Wang, H. in: JCI | PubMed | Google Scholar

Published September 3, 2024 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.179871.
Copyright © 2024, Li et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published September 3, 2024 - Version history
View PDF
Abstract

The prevalence of chronic kidney diseases (CKD) varies by race due to genetic and environmental factors. The Glu504Lys polymorphism in aldehyde dehydrogenase 2 (ALDH2), commonly observed among East Asians, alters the enzyme's function in detoxifying alcohol-derived aldehydes, impacting kidney function. This study investigated the association between variations in ALDH2 levels within the kidney and the progression of kidney fibrosis. Our clinical data indicates that diminished ALDH2 levels are linked to worse CKD outcomes, with correlations between ALDH2 expression, estimated glomerular filtration rate, urinary levels of acrolein, an aldehyde metabolized by ALDH2, and fibrosis severity. In mouse models of unilateral ureteral obstruction and folic acid nephropathy, reduced ALDH2 levels and elevated acrolein were observed in kidneys, especially in ALDH2 Glu504Lys knock-in mice. Mechanistically, acrolein modifies pyruvate kinase M2, leading to its nuclear translocation and co-activation of HIF-1α, shifting cellular metabolism to glycolysis, disrupting mitochondrial function, contributing to tubular damage and the progression of kidney fibrosis. Enhancing ALDH2 expression through adeno-associated virus vectors reduces acrolein and mitigates fibrosis in both wild-type and Glu504Lys knock-in mice. These findings underscore the potential therapeutic significance of targeting the dynamic interaction between ALDH2 and acrolein in CKD.

Graphical Abstract
graphical abstract
Supplemental material

View Unedited blot and gel images

View

Version history
  • Version 1 (September 3, 2024): In-Press Preview
Advertisement
Advertisement