Pitavastatin attenuates cisplatin-induced renal injury by targeting MAPK and apoptotic pathways Swati Kaushik a,† , Ameesha Tomar a,† , Susrutha Puthanmadhom Narayanan a , Tapas Chandra Nag b , Dharamvir Singh Arya a and Jagriti Bhatia a a Cardiovascular Research Laboratory, Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India and b Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India Keywords cisplatin; MAPK; nephrotoxicity; pitavastatin Correspondence Jagriti Bhatia, Department of Pharmacology, All India Institute of Medical Sciences, New Delhi 110029, India. E-mail: jagriti2012@gmail.com Received August 16, 2018 Accepted March 9, 2019 doi: 10.1111/jphp.13090 † These authors contributed equally to the research. Abstract Objective Anti-neoplastic drug cisplatin is prescribed widely for treatment of a variety of malignancies. Its use has been restricted lately due to severe renal toxic- ity. The purpose of current study was to investigate the effect of pitavastatin (a hypolipidaemic drug) in cisplatin-induced acute kidney injury in rats. Method Male Wistar rats (150–200 g) were treated with different doses of pitavastatin (0.16, 0.32 and 0.64 mg/kg per day p.o.; 10 days). On 7th day of the study, rats were administered cisplatin (8 mg/kg i.p.). Rats were euthanized (11th day), and blood and tissues were processed to evaluate biochemical, histopathological and ultrastructural parameters along with the analysis of immunohistochemistry and DNA-fragmentation studies. Protein expressions were analysed to demonstrate the underlying molecular mechanisms. Key findings In the study group with cisplatin insult, KFT parameters were found to be elevated, concentration of apoptotic markers was found to be increased, histopathological and ultramicroscopical architecture was found to be distorted and the expression of MAPK proteins was also found to be elevated as compared to the normal group rats. Pitavastatin treatment alleviated all these anomalies. Conclusion Cisplatin-induced acute renal injury was improved on administra- tion of pitavastatin via inhibition of MAPK and apoptotic pathway. Introduction Cisplatin is a highly potent chemotherapeutic agent used for solid tumours such as testicular cancer, ovarian cancer, head and neck cancer and lung cancer. In spite of excellent cure rates with cisplatin-based regimens, their use is associated with several dose-limiting adverse effects such as nausea, vomiting, nephrotoxicity, dyselectrolytemia, neurotoxicity, ototoxicity and myelosuppression. [1–4] The existing guideli- nes to address cisplatin-induced nephrotoxicity include dose adjustment based on creatinine clearance, hydration and concomitant use of amifostine. These preventive measures are not satisfactory especially when repeated doses need to be administered. [5] This warrants the need for more efficient strategies to suppress this renal injury. It is well known that renal proximal tubule cells exhibit maximal toxic damage due to cisplatin as they selectively accumulate cisplatin. The anti-neoplastic effect of cisplatin is mediated by formation of inter- and intrastrand DNA cross- links, which initiate the DNA damage repair (DDR) cascade resulting in cell cycle arrest and cell apoptosis. Even though this mechanism could partly be implicated, [6] it is insufficient by itself to explain the renal damage caused by cisplatin. The role of oxidative stress, inflammation, pro-apoptotic sig- nalling and cellular pathways such as the mitogen-activated protein kinases (MAPKs) has been elucidated in the damage caused by the accumulated drug. [6–8] MAPKs act as promi- nent signal transduction system that mediates cellular response to stressors such as reactive oxygen species, ischae- mia and inflammatory cytokines. These findings have been validated by various experiments from our laboratory using rat models. [9,10] An ideal molecule to treat cisplatin-induced nephrotoxicity should reverse the aforementioned changes, without blunting its cytotoxic effects on malignant cells. © 2019 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 71 (2019), pp. 1072–1081 1072 Research Paper Downloaded from https://academic.oup.com/jpp/article/71/7/1072/6122047 by guest on 26 November 2023