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

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL JCI insight Pub Date : 2024-10-08 DOI:10.1172/jci.insight.179871
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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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.

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醛脱氢酶 2 通过对抗丙烯醛引起的代谢和线粒体功能障碍来保护肾功能。
由于遗传和环境因素,慢性肾脏疾病(CKD)的发病率因种族而异。醛脱氢酶 2(ALDH2)中的 Glu504Lys 多态性在东亚人中很常见,它会改变该酶对酒精衍生的醛的解毒功能,从而影响肾功能。本研究调查了肾脏中 ALDH2 水平的变化与肾脏纤维化进展之间的关系。我们的临床数据表明,ALDH2 水平的降低与慢性肾脏病恶化的结果有关,ALDH2 表达、估计肾小球滤过率、尿液中的丙烯醛(一种由 ALDH2 代谢的醛)水平和纤维化严重程度之间存在相关性。在单侧输尿管梗阻和叶酸肾病小鼠模型中,观察到肾脏中 ALDH2 水平降低,丙烯醛升高,尤其是在 ALDH2 Glu504Lys 基因敲入小鼠中。从机理上讲,丙烯醛会改变丙酮酸激酶 M2,导致其核转位并共同激活 HIF-1α,使细胞代谢转向糖酵解,破坏线粒体功能,导致肾小管损伤和肾脏纤维化的进展。通过腺相关病毒载体增强 ALDH2 的表达,可减少丙烯醛并减轻野生型小鼠和 Glu504Lys 基因敲入小鼠的纤维化。这些发现强调了针对 CKD 中 ALDH2 和丙烯醛之间动态相互作用的潜在治疗意义。
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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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