Aldehyde dehydrogenase 2 preserves kidney function by countering acrolein-induced metabolic and mitochondrial dysfunction
Szu-Yuan Li, Ming-Tsun Tsai, Yu-Ming Kuo, Hui-Min Yang, Zhen-Jie Tong, Hsiao-Wei Cheng, Chih-Ching Lin, Hsiang-Tsui Wang
Szu-Yuan Li, Ming-Tsun Tsai, Yu-Ming Kuo, Hui-Min Yang, Zhen-Jie Tong, Hsiao-Wei Cheng, Chih-Ching Lin, Hsiang-Tsui Wang
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Research Article Metabolism Nephrology

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

Abstract

The prevalence of chronic kidney disease (CKD) varies by race because of genetic and environmental factors. The Glu504Lys polymorphism in aldehyde dehydrogenase 2 (ALDH2), commonly observed among East Asian people, alters the enzyme’s function in detoxifying alcohol-derived aldehydes, affecting kidney function. This study investigated the association between variations in ALDH2 levels within the kidney and the progression of kidney fibrosis. Our clinical data indicate 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–knockin mice. Mechanistically, acrolein modifies pyruvate kinase M2, leading to its nuclear translocation and coactivation of HIF-1α, shifting cellular metabolism to glycolysis, disrupting mitochondrial function, and contributing to tubular damage and the progression of kidney fibrosis. Enhancing ALDH2 expression through adeno-associated virus vectors reduced acrolein and mitigated fibrosis in both WT and Glu504Lys-knockin mice. These findings underscore the potential therapeutic significance of targeting the dynamic interaction between ALDH2 and acrolein in CKD.

Authors

Szu-Yuan Li, Ming-Tsun Tsai, Yu-Ming Kuo, Hui-Min Yang, Zhen-Jie Tong, Hsiao-Wei Cheng, Chih-Ching Lin, Hsiang-Tsui Wang

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Figure 6

Acrolein-modified PKM2 shifts mitochondrial oxidative phosphorylation to aerobic glycolysis in NRK-52E cells and primary mouse renal tubular epithelial cells.

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Acrolein-modified PKM2 shifts mitochondrial oxidative phosphorylation to...
(A–C) NRK-52E cells were exposed to acrolein (0–30 μM) for 24 hours. (A) Western blot analysis of Acr-PCs is presented. (B) Tandem mass spectrometry illustrating the acrolein-modified peptide in acrolein-treated NRK-52E cells. (C) Pyruvate kinase (PK) activity was determined. (D) Immunofluorescence staining of PKM2 in acrolein-treated NRK-52E cells. Scale bar: 10 μm. (E) Subcellular localization of PKM2 in acrolein-treated NRK-52E cells. Cells treated with acrolein (20 μM, 24 hours) were subjected to the Cell Fractionation Kit, followed by Western blot analysis. (F) Co-immunoprecipitation analysis of nuclear fractions prepared from acrolein-treated NRK-52E cells using an anti-PKM2 antibody or IgG antibody, followed by Western blot analysis. (G) Cells treated with acrolein (20 μM, 24 hours) were subjected to chromatin immunoprecipitation (ChIP) assays with antibodies against HIF-1α (the left panel), PKM2 (the right panel), or IgG, followed by real-time quantitative PCR for PDK1 and HXK2. (H) NRK-52E cells treated with acrolein (0–30 μM) for 24 hours were subjected to Western blot analysis with quantification. (I) Primary renal tubular epithelial cells isolated from Aldh2 WT or Aldh2*2/*2 mice treated with acrolein (0–30 μM) for 24 hours were subjected to Western blot analysis with quantification. (J) Oxygen consumption rate (OCR) was analyzed using the Seahorse XFe24 Metabolic Flux Analyzer. (K and L) ALDH2 overexpression in NRK-52E cells using AAV8-ALDH2-EGFP transient transfection for 24 hours followed by acrolein treatment (20 μM, 24 hours). Western blot analysis was performed. Data are presented as mean ± SD. Statistical significance was determined using Kruskal-Wallis tests, with 2-tailed P values indicated. *P < 0.05, **P < 0.01, ***P < 0.001 compared with vehicle treatment. Acr-PCs, acrolein-protein conjugates; PKM2, pyruvate kinase M2; HXK2, hexokinase 2; PDK1, pyruvate dehydrogenase kinase 1.