Suppression of aldehyde dehydrogenase 2 in kidney proximal tubules contributes to kidney fibrosis through Transforming Growth Factor-β signaling

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.