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Aldehyde dehydrogenase 2 alleviates mitochondrial dysfunction by promoting PGC-1α-mediated biogenesis in acute kidney injury
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Aldehyde dehydrogenase 2 alleviates mitochondrial dysfunction by promoting PGC-1α-mediated biogenesis in acute kidney injury
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Journal Article
Aldehyde dehydrogenase 2 alleviates mitochondrial dysfunction by promoting PGC-1α-mediated biogenesis in acute kidney injury
2023
Overview
Renal tubular epithelial cells are one of the high energy-consuming cell types, which mainly depend on mitochondrial energy supply. Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme that is involved in alcohol metabolism and mitochondrial oxidative ATP production; however, its function in mitochondrial homoeostasis in acute kidney injury (AKI) is unclear. Here, we found that ALDH2 expression was predominantly decreased in cisplatin or maleic acid (MA) models both in vivo and in vitro.
ALDH2
knockout (KO) mice exhibited exacerbated kidney impairment and apoptosis of tubular epithelial cells after cisplatin injection. In contrast, ALDH2 activation alleviated AKI and tubular cell apoptosis in both cisplatin- and MA-induced models. RNA sequencing revealed that the oxidative phosphorylation pathway was positively enriched in the renal tissues after Alda-1 pre-treatment in MA-induced mice. ALDH2 activation restored mitochondrial structure, mitochondrial membrane potential, and respiration rate, but downregulated glycolysis in MA-induced mice and human renal proximal tubular epithelial (HK-2) cells. Mechanistically, co-immunoprecipitation assays revealed that ALDH2 interacts with peroxisomal proliferator-γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis, and advanced its nuclear translocation. Subsequently,
PGC-1α
knockdown almost abolished the improvement of ALDH2 activation on MA-induced tubular epithelial cells damage. Thus, our study revealed that ALDH2 activation alleviated mitochondrial dysfunction in AKI by enhancing PGC-1α-mediated mitochondrial biogenesis. Hence, ALDH2 may act as a potential therapeutic target to prevent AKI progression.
Publisher
Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
Subject
/ 14
/ 38
/ 692/420
/ 692/699
/ 96
/ Acute Kidney Injury - chemically induced
/ Acute Kidney Injury - genetics
/ Acute Kidney Injury - metabolism
/ Aldehyde Dehydrogenase - metabolism
/ Aldehyde Dehydrogenase, Mitochondrial - genetics
/ Aldehyde Dehydrogenase, Mitochondrial - metabolism
/ Animals
/ Biomedical and Life Sciences
/ Humans
/ Kidneys
/ Mice
/ Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - genetics
/ Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism
