慢性肾病（CKD）是一种日益流行的疾病，给全球健康和社会经济带来了巨大的负担。与西方国家相比，中国、台湾、日本和韩国等东亚国家的肾衰竭发病率和患病率较高，但造成这种差异的原因尚不清楚。醛脱氢酶 2 (ALDH2) 是线粒体外源性和内源性醛代谢所必需的解毒酶。 E504K 和 E487K 失活突变存在于 35-45% 的东亚人群中，并且与各种疾病（包括心血管疾病和癌症）的较高风险相关。然而，人们对 ALDH2 在 CKD 中的作用知之甚少。在这里，我们表征了正常和 CKD 人和小鼠肾脏中 ALDH2 的表达模式，并证明 ALDH2 表达显着降低，并且蛋白水平与 CKD 和纤维化程度呈负相关。此外，我们用马兜铃酸治疗 ALDH2*2 敲入小鼠（ALDH2 功能丧失模型），发现这些小鼠的纤维化程度增强。此外，ALDH2 缺乏与肾纤维化有关，涉及体内和体外上皮细胞分化过程。然而，ALDH2 过表达可保护近端肾小管上皮细胞免于体外转化生长因子-β 诱导的去分化或部分上皮间质转分化。因此，我们的研究结果提供了有关涉及 ALDH2 的 CKD 发生和进展的重要临床信息，尤其是在东亚人群中。版权所有 © 2024 国际肾病学会。由爱思唯尔公司出版。保留所有权利。

Chronic kidney disease (CKD) is an increasingly prevalent disorder that poses a significant global health and socioeconomic burden. East Asian countries such as China, Taiwan, Japan, and South Korea have a higher incidence and prevalence of kidney failure when compared to Western nations, and the reasons for this discrepancy remain unclear. Aldehyde dehydrogenase 2 (ALDH2) is an essential detoxifying enzyme for exogenous and endogenous aldehyde metabolism in mitochondria. Inactivating mutations at E504K and E487K are found in 35-45% of East Asian populations and has been linked to a higher risk of various disorders, including cardiovascular diseases and cancer. However, little is known about the role of ALDH2 in CKD. Here, we characterized the expression pattern of ALDH2 in normal and CKD human and mouse kidneys and demonstrated that ALDH2 expression was significantly reduced, and that the protein level was inversely correlated with the degree of CKD and fibrosis. Further, we treated ALDH2*2 knock-in mice, a loss of ALDH2 function model, with aristolochic acid and found that these mice showed enhanced fibrosis. Moreover, ALDH2 deficiency was associated with kidney fibrosis involving epithelial cell differentiation process in vivo and in vitro. However, ALDH2 overexpression protected proximal tubule epithelial cells from transforming growth factor-β-induced dedifferentiation or partial epithelial-mesenchymal transdifferentiation in vitro. Thus, our findings yield important clinical information regarding the development and progression of CKD involving ALDH2, especially among East Asian populations.Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.