VALD-2 mitigates cisplatin-induced acute kidney injury: Mechanistic insights into oxidative stress modulation and inflammation suppression.

Abstract

This study explores the compelling antitumor properties of VALD-2, a synthetic Schiff base ligand known for its low toxicity. The focus is on investigating VALD-2's protective role against cisplatin-induced acute kidney injury (AKI) in mice, with a specific emphasis on mitigating oxidative stress and inflammation. The study involves daily intraperitoneal injections of amifostine or VALD-2 over 7 days to establish an AKI model. Subsequently, mice were assigned to normal control, cisplatin group, cisplatin + amifostine group, and cisplatin + VALD-2 10 mg/kg group, cisplatin + VALD-2 20 mg/kg, and cisplatin + VALD-2 40 mg/kg. Kidney injury is assessed through serum blood urea nitrogen (BUN) and creatinine (Cr) activity assays. Levels of inflammatory factors,tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), in kidney tissue of mice were assessed through enzyme-linked immunosorbent assay (ELISA). The protective effect of VALD-2 is further examined through HE staining to observe pathological changes in kidney injury. The ultrastructural changes of renal cells and tubular epithelial cells were observed by electron microscopy under experimental conditions, indicating the effect of VALD-2 on reversing cisplatin-induced renal injury. The study delves into VALD-2's protective mechanisms against cisplatin-induced kidney injury by using western blot analysis to assess the expression levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA) in kidney tissues. VALD-2 demonstrates significant improvement in cisplatin-induced AKI, as evidenced by increased BUN and Cr levels. It effectively protects kidney tissue from oxidative damage, enhancing SOD and GSH-Px activities while reducing MDA levels. The study also reveals a decrease in TNF-α and IL-6 levels, supported by ELISA results, and histological findings confirm anti-nephrotoxic effects. Western blot analysis shows an upregulation of antioxidant enzymes (SOD, GSH-Px) and a reduction in MDA production. VALD-2 emerges as a promising mitigator of cisplatin-induced AKI, showcasing its ability to enhance oxidative stress-related protein expression. The findings suggest VALD-2 as a potential therapeutic agent for protecting against cisplatin-induced kidney injury.