Pharmaceuticals
HDAC2 Partially Contributes to the Differential Nephrotoxicity Induced by AA-I, AA-IVa, or AL-I
Par Yuxing Wang, Xian Zhong, Jing Meng et 17 autres.
Contenu en anglais
Résumé
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.