Elsevier

European Journal of Pharmacology

Volume 748, 5 February 2015, Pages 54-60
European Journal of Pharmacology

Cardiovascular pharmacology
Telmisartan ameliorates cisplatin-induced nephrotoxicity by inhibiting MAPK mediated inflammation and apoptosis

https://doi.org/10.1016/j.ejphar.2014.12.008Get rights and content

Abstract

Nephrotoxicity is a major adverse effect of the widely used anticancer drug cisplatin. Oxidative stress, inflammation and apoptosis are implicated in the pathophysiology of cisplatin-induced acute renal injury. Moreover, cisplatin activates many signal transduction pathways involved in cell injury and death, particularly mitogen activated protein kinase (MAPK) pathway. With this background, we aimed to investigate the protective effect of telmisartan, a widely used antihypertensive drug, in cisplatin-induced nephrotoxicity model in rats. To accomplish this, male albino wistar rats (150–200 g) were divided into 6 groups: Normal, cisplatin-control, telmisartan (2.5, 5 and 10 mg/kg) and telmisartan per se treatment groups. Normal saline or telmisartan was administered orally to rats for 10 days and cisplatin was given on 7th day (8 mg/kg; i.p.) to induce nephrotoxicity. On 10th day, rats were killed and both the kidneys were harvested for biochemical, histopathological and molecular studies. Cisplatin injected rats showed depressed renal function, altered proxidant–antioxidant balance and acute tubular necrosis which was significantly normalized by telmisartan co-treatment. Furthermore, cisplatin administration activated MAPK pathway that caused tubular inflammation and apoptosis in rats. Telmisartan treatment significantly prevented MAPK mediated inflammation and apoptosis. Among the three doses studied telmisartan at 10 mg/kg dose showed maximum nephroprotective effect which could be due to maintenance of cellular redox status and inhibition of MAPK activation.

Introduction

Cisplatin (cis-diamminedichloroplatinum) is one of the most effective anticancer drugs used for the treatment of solid cancers of head, neck, testicular, ovarian, cervical and non-small cell lung carcinoma. However, it is associated with dose-limiting nephrotoxicity that occurs in approximately one third of the patients. Cisplatin primarily accumulates in proximal straight and distal convoluted tubules causing cellular damage and impairment of renal function (Terada et al., 2013). Various approaches attempting to limit this side effect have failed and the only treatment available at present is to hydrate the patients with saline and induce diuresis; nevertheless, the effect is only partial and still over a quarter of patients experience renal problems or insufficiency. Thus, it is necessary to investigate newer measures for preventing this dose-limiting side effect of cisplatin, especially when it has to be given at high tumoricidal doses for a long duration.

Multiple mechanisms have been implicated in the pathophysiology of cisplatin-induced renal injury such as oxidative stress, apoptosis and inflammation. Of late, there is growing evidence that members of mitogen activated protein kinases (MAPKs) family; such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 are activated after cisplatin administration and contribute to renal cell death (Pabla and Dong, 2008). Nowak demonstrated that cisplatin induced phosphorylation and accumulation of ERK1/2 in the mitochondria of renal proximal tubular cells. Further, administration of ERK1/2 pharmacological inhibitors – PD98059 and U1026 – prevented ERK1/2 mediated cytochrome c release, caspase-3 activation and translocation of Bax from cytoplasm to mitochondria, and attenuated cisplatin-induced mitochondrial dysfunction (Nowak, 2002). The role of p38 in nephrotoxicity was highlighted by Francescato et al. They showed that blockade of p38 MAPK activation decreased cisplatin mediated inflammation, oxidative stress and apoptotic cell death in kidney (Francescato et al., 2009). However, the role of JNK in cisplatin-induced renal injury is not well characterized but a recent work by Kim et al. (2014), demonstrated that activation of JNK (phospho-JNK) deteriorated renal function, increased tubular inflammation and apoptosis after cisplatin administration, suggesting a mechanistic role of JNK in acute kidney injury. Hence, these observations by various workers suggest that MAPK pathway can be used as a potential target to explore newer therapeutic interventions to curtail cisplatin-induced nephrotoxicity.

Telmisartan is a potent, long-acting, nonpeptide angiotensin II type-1 (AT1) receptor antagonist that has shown anti-inflammatory, antioxidant, anti-apoptotic and nephroprotective effects (Fouad et al., 2010). Many preclinical studies have demonstrated its protective role in doxorubicin-induced nephrotoxicity (Ibrahim et al., 2009), partially nephrectomized rats (Tsunenari et al., 2007), X-ray contrast media induced nephrotoxicity (Duan et al., 2009), renal ischemia–reperfusion injury (Fouad et al., 2010), cadmium-induced nephrotoxicity (Fouad and Jresat, 2011; Ahmed, 2013), and diabetic nephropathy (Ohmura et al., 2012). Also, few clinical studies have confirmed its protective effect against diabetic nephropathy (Barnett, 2005) and hypertensive non-diabetic nephropathy (Aranda et al., 2005). However, there is no study addressing its role in cisplatin-induced acute renal injury. Hence, the present experimental study was conducted to evaluate its renoprotective potential in cisplatin-induced nephrotoxicity and further to investigate whether MAPK pathway mediates this nephroprotection.

Section snippets

Animals

The study was carried out on 36 male albino wistar rats, each weighing 150–200 g. The current study was approved by Institutional Animal Ethics Committee of All India Institute of Medical Sciences, New Delhi, India, (IAEC No. 715/13), and all experimental procedures were conducted in accordance to Indian National Science Academy Guidelines for Care and Use of Animals in Scientific research. The animals were housed in standard laboratory conditions at a constant temperature (25±2 °C) with a

Effect of telmisartan on renal function

Serum creatinine and BUN levels were measured to evaluate whether telmisartan treatment preserved kidney function. Cisplatin-control group exhibited significant increase in serum creatinine (P<0.01) and BUN (P<0.001) levels as compared to normal group. This suggests that cisplatin induced significant kidney injury. On the contrary, telmisartan pretreatment normalized the levels of creatinine and BUN in serum with respect to cisplatin-control group. The significant stabilization of these

Discussion

The present study demonstrated that telmisartan reduced oxidative stress mediated MAPK activation, which in turn controlled inflammation and apoptosis in renal tubular cells. Together, it ameliorated cisplatin-induced nephrotoxicity and preserved renal function (Fig. 4). Cisplatin is a chemotherapeutic agent widely used for the treatment of various solid-organ cancers but unfortunately, it causes dose-dependent nephrotoxicity that often requires dose reduction or withdrawal. Several reports

Conclusion

Thus, it can be concluded that telmisartan attenuated cisplatin-induced nephrotoxicity by inhibiting MAPK mediated apoptosis and inflammation. Further, it reduced the renal oxidative stress and improved renal function and morphology. Our study provides a good ground to consider telmisartan as one of the drug candidate options to be further elucidated for its role in preventing cisplatin-induced acute renal injury in humans.

Acknowledgement

The authors are grateful to Mr. BM Sharma for his technical assistance and to All India Institute of Medical Sciences, New Delhi (Grant No. A-175) for financial assistance to conduct study.

References (31)

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