Pharmaceuticals
HDAC2 Partially Contributes to the Differential Nephrotoxicity Induced by AA-I, AA-IVa, or AL-I
By Yuxing Wang, Xian Zhong, Jing Meng and 17 others.
Abstract
Background
ASARI RADIX ET RHIZOMA (Xixin), extensively utilized in clinical settings, contains aristolochic acid analogs (AAAs), primarily AA-IVa, with minor quantities of AL-I and negligible levels of AA-I. AA-I mediates aristolochic acid-induced nephropathy; therefore, the safety of Xixin is controversial. The toxicity of AAAs is varied, and the mechanisms are ambiguous.
Objective
To compare the toxicity of AA-I, AA-IVa, and AL-I toward renal tubular epithelial cells and explain the molecular causes of such. Materials and Methods: C57BL/6 mice were administered AA-I, AA-IVa, or AL-I for 24 weeks; renal toxicity was assessed via survival and histopathology. In vitro, AAAs toxicity was evaluated in human renal tubular epithelial cells (HK-2) by high-content Hoechst 33342/PI apoptotic tests and fibrosis marker quantification. Transcriptomics revealed alterations in genes and pathways induced by AAAs. Click chemistry-based activity-based protein profiling, molecular docking, surface plasmon resonance, enzyme activity assays, and gene knockdown identified the AAAs’ direct targets.