title: Telmisartan ameliorates cisplatin-induced nephrotoxicity by inhibiting MAPK mediated inflammation and apoptosis.
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.
authors.affiliation: Department of Pharmacology, Cardiovascular Research Laboratory, All India Institute of Medical Sciences, New Delhi-110029, India.
authors.forename: Salma
authors.initials: S
authors.lastname: Malik
authors.affiliation: Department of Pharmacology, Cardiovascular Research Laboratory, All India Institute of Medical Sciences, New Delhi-110029, India.
authors.forename: Kapil
authors.initials: K
authors.lastname: Suchal
authors.affiliation: Department of Pharmacology, Cardiovascular Research Laboratory, All India Institute of Medical Sciences, New Delhi-110029, India.
authors.forename: Nanda
authors.initials: N
authors.lastname: Gamad
authors.affiliation: Department of Pathology, All India Institute of Medical Sciences, New Delhi-110029, India.
authors.forename: Amit Kumar
authors.initials: AK
authors.lastname: Dinda
authors.affiliation: Department of Pharmacology, Cardiovascular Research Laboratory, All India Institute of Medical Sciences, New Delhi-110029, India.
authors.forename: Dharamvir Singh
authors.initials: DS
authors.lastname: Arya
authors.affiliation: Department of Pharmacology, Cardiovascular Research Laboratory, All India Institute of Medical Sciences, New Delhi-110029, India. Electronic address: jagriti2012@rediffmail.com.
authors.forename: Jagriti
authors.initials: J
authors.lastname: Bhatia
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects*; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D001565:Benzoates / Q000494:pharmacology* / Q000627:therapeutic use; D002945:Cisplatin / Q000009:adverse effects*; D019610:Cytoprotection / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D000077333:Telmisartan; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D001565:Benzoates; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D002945:Cisplatin; D000077333:Telmisartan
keywords: ERK1/2; JNK; Oxidative stress; TNF-α; p38