Upregulation of Thioredoxin Reductase 1 Expression by Flavan-3-Ols Protects Human Kidney Proximal Tubular Cells from Hypoxia-Induced Cell Death

Renal hypoxia and its associated oxidative stress is a common pathway for the development of kidney diseases, and using dietary antioxidants such as flavan-3-ols to prevent kidney failure has received much attention. This study investigates the molecular mechanism by which flavan-3-ols prevent hypoxia-induced cell death in renal tubular epithelial cells. Human kidney proximal tubular cells (HKC-8) were exposed to hypoxia (1% O₂) in the presence of flavan-3-ols (catechin, epicatechin, procyanidin B1, and procyanidin B2). Cell death was examined using flow cytometric analysis. Gene expression was determined using a PCR array and Western blotting, and its network and functions were investigated using STRING databases. Here, we show that the cytoprotective activity of catechin was the highest among these flavan-3-ols against hypoxia-induced cell death in cultured HKC-8 cells. Exposure of HKC-8 cells to hypoxia induced oxidative stress leading to up-regulation of DUOX2, NOX4, CYBB and PTGS2 and down-regulation of TXNRD1 and HSP90AA1. Treatment with catechin or other flavan-3-ols prevented the down-regulation of TXNRD1 expression in hypoxic HKC-8 cells. Overexpression of TXNRD1 prevented hypoxia-induced cell death, and inactivation of TXNRD1 with TRi-1, a specific TXNRD1 inhibitor, reduced the catechin cytoprotection against hypoxia-induced HKC-8 cell death. In conclusion, flavan-3-ols prevent hypoxia-induced cell death in human proximal tubular epithelial cells, which might be mediated by their maintenance of TXNRD1 expression, suggesting that enhancing TXNRD1 expression or activity may become a novel therapeutic strategy to prevent hypoxia-induced kidney damage.