Aristolochic acid-induced DNA adduct formation triggers acute DNA damage response in rat kidney proximal tubular cells

Abstract

Aristolochic acid nephropathy (AAN) is a form of acute kidney injury triggered by the ingestion of aristolochic acid (AA), characterized by significant degeneration and loss of cells in the proximal tubules. Previous reports of AA-induced acute kidney injury have reported that AA-induced cytotoxicity can occur within a short period, up to 24 h; however, there are few reports on the relationship between AA-DNA adduct formation and cytotoxic mechanism during the acute phase. In this study, we aimed to elucidate the toxicological mechanisms in the initial phase of AA exposure by examining the effects of AA on NRK-52E rat proximal tubular cells within 24 h. We detected the formation of AA-DNA adducts as early as 4 h post-exposure, indicating that 50 μM of AA causes DNA damage. The DNA damage response pathway was activated, peaking at 8 h post-exposure. Additionally, we observed an increasing trend of G1 phase cell cycle arrest after 8 h, followed by a significant decline in cell viability at 16 h. These findings suggest that 50 μM of AA induces rapid DNA damage in NRK-52E cells, primarily through the formation of AA-DNA adducts, ultimately leading to G1 phase cell cycle arrest.