Abstract

Cisplatin is an effective chemotherapeutic agent, but its clinical use is frequently limited by its nephrotoxicity. The pathogenesis of cisplatin-induced acute kidney injury (AKI) remains incompletely understood, but oxidative stress, tubular cell death, and inflammation are considered important contributors to cisplatin-induced renal injury. Kahweol is a natural diterpene extracted from coffee beans and has been shown to possess anti-oxidative and anti-inflammatory properties. However, its role in cisplatin-induced nephrotoxicity remains undetermined. Therefore, we investigated whether kahweol exerts a protective effect against cisplatin-induced renal injury. Additionally, its mechanisms were also examined. Administration of kahweol attenuated renal dysfunction and histopathological damage together with inhibition of oxidative stress in cisplatin-injected mice. Increased expression of nicotinamide adenine dinucleotide phosphate oxidase 4 and decreased expression of manganese superoxide dismutase and catalase after cisplatin treatment were significantly reversed by kahweol. Moreover, kahweol inhibited cisplatin-induced apoptosis and necroptosis in the kidneys. Finally, kahweol reduced inflammatory cytokine production and immune cell accumulation together with suppression of nuclear factor kappa-B pathway and downregulation of vascular adhesion molecules. Together, these results suggest that kahweol ameliorates cisplatin-induced renal injury via its pleiotropic effects and might be a potential preventive option against cisplatin-induced nephrotoxicity.

Highlights

  • Cisplatin is a platinum-containing chemotherapeutic agent that has been widely used for the treatment of various human cancers [1]

  • Thesecytokines increases were attenuated byBecause kahweol (Figure levels of these were markedly increased in cisplatin-injected mice (Figure the production of cytokines, we examined the effects of kahweol on Khaweol plays an essential role in the production of cytokines, we examined the effects of kahweol on these increases were significantly attenuated by kahweol (Figure 9A–C)

  • Our findings suggest that kahweol inhibited oxidative stress and thereby inhibited tubular cell apoptosis in cisplatin-induced renal injury

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Summary

Introduction

Cisplatin is a platinum-containing chemotherapeutic agent that has been widely used for the treatment of various human cancers [1]. Its clinical use is frequently limited due to its side effects. Acute kidney injury (AKI) is the most common dose-limiting side effect of cisplatin treatment. About a third of patients on cisplatin treatment suffer from the nephrotoxic side effect [1]. No effective therapies for cisplatin-induced AKI are currently available. It is essential to develop therapeutic agents for preventing nephrotoxicity, enabling high-dose chemotherapy using cisplatin

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