Mitigation of cisplatin-induced nephrotoxicity by chelidonic acid in Wistar rats

Abstract

Introduction: Cisplatin, an anti-cancer drug is used to treat a wide range of solid tumors. Nevertheless, nephrotoxicity is the major adverse effect that restricts its clinical application. The present study focuses on the effect of chelidonic acid in cisplatin-induced nephrotoxicity.

Methods: Wistar rats were injected with cisplatin (5 mg/kg, intraperitoneally (i.p.), once in a week for 4 weeks) and chelidonic acid (10, 20, and 40 mg/kg, per oral (p.o.) for 4 weeks). Body weight, urine, biochemical, and oxidative stress parameters were performed to evaluate the effect of chelidonic acid in cisplatin-induced nephrotoxicity in rats. Pro-inflammatory cytokines and nuclear factor erythroid 2-related factor 2 (Nrf2) concentrations were determined. Expression of phospho-AMP activated protein kinase (phospho-AMP) and hypoxia-inducible factor 1-alpha (HIF-1α) was studied with western blot. Haematoxylin and eosin, periodic acid-Schiff, and Masson's trichrome staining were used to study kidney tissues.

Results: Relative kidney weight and urine output were significantly increased in cisplatin-administered rats. Whereas, albumin, and creatinine concentration were decreased, and treatment with chelidonic acid reverses these deleterious effects of cisplatin significantly. Kidney functions were improved by chelidonic acid treatment with a reduction in tumor necrosis factor-alpha (TNF-α), Interleukin-6 (IL-6), and transforming growth factor-beta (TGF-β1) concentration. The oxidative stress was decreased as compared to the cisplatin group. Furthermore, Nrf2 was significantly increased by chelidonic acid treatment. Chelidonic acid treatment significantly increased the expression of phospho-AMPK and HIF-1α in kidney tissue. Histopathological studies revealed that chelidonic acid reduced kidney damage.

Conclusion: The findings showed that chelidonic acid increases phospho-AMPK and HIF-1α in the kidney tissue and significantly lowers the inflammatory cytokines, thus it is an effective molecule for providing protection against cisplatin-induced nephrotoxicity.

Keywords: Chelidonic acid; Cisplatin; Cytokines; Nephrotoxicity; Nrf2.