title: Inhibition of PARP activation by enalapril is crucial for its renoprotective effect in cisplatin-induced nephrotoxicity in rats.
abstract: Oxidative stress-induced PARP activation has been recognized to be a main factor in the pathogenesis of cisplatin-induced nephrotoxicity. Accumulating literature has revealed that ACE inhibitors may exert beneficial effect in several disease models via preventing PARP activation. Based on this hypothesis, we have evaluated the renoprotective effect of enalapril, an ACE inhibitor, and its underlying mechanism(s) in cisplatin-induced renal injury in rats. Male Albino Wistar rats were orally administered normal saline or enalapril (10, 20 and 40 mg/kg) for 10 days. Nephrotoxicity was induced by a single dose of cisplatin (8 mg/kg; i.p.) on the 7th day. The animals were thereafter sacrificed on the 11th day and both the kidneys were excised and processed for biochemical, histopathological, molecular, and immunohistochemical studies. Enalapril (40 mg/kg) significantly prevented cisplatin-induced renal dysfunction. In comparison to cisplatin-treated group, the elevation of BUN and creatinine levels was significantly less in this group. This improvement in kidney injury markers was well substantiated with reduced PARP expression along with phosphorylation of MAPKs including JNK/ERK/p38. Enalapril, in a dose-dependent fashion, attenuated cisplatin-induced oxidative stress as evidenced by augmented GSH, SOD and catalase activities, reduced TBARS and oxidative DNA damage (8-OHDG), and Nox-4 protein expression. Moreover, enalapril dose dependently inhibited cisplatin-induced inflammation (NF-κB/IKK-β/IL-6/Cox-2/TNF-α expressions), apoptosis (increased Bcl-2 and reduced p53, cytochrome c, Bax and caspase-3 expressions, and TUNEL/DAPI positivity) and preserved the structural integrity of the kidney. Thus, enalapril attenuated cisplatin-induced renal injury via inhibiting PARP activation and subsequent MAPKs/TNF-α/NF-κB mediated inflammatory and apoptotic response.
authors: a Department of Pharmacology , All India Institute of Medical Sciences , New Delhi , India.
authors: Neha
authors: N
authors: Rani
authors: a Department of Pharmacology , All India Institute of Medical Sciences , New Delhi , India.
authors: Saurabh
authors: S
authors: Bharti
authors: a Department of Pharmacology , All India Institute of Medical Sciences , New Delhi , India.
authors: Ameesha
authors: A
authors: Tomar
authors: b Department of Pathology , All India Institute of Medical Sciences , New Delhi , India.
authors: Amit Kumar
authors: AK
authors: Dinda
authors: a Department of Pharmacology , All India Institute of Medical Sciences , New Delhi , India.
authors: D S
authors: DS
authors: Arya
authors: a Department of Pharmacology , All India Institute of Medical Sciences , New Delhi , India.
authors: Jagriti
authors: J
authors: Bhatia
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002945:Cisplatin / Q000009:adverse effects*; D004656:Enalapril / Q000008:administration & dosage / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects*; D018384:Oxidative Stress; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000970:Antineoplastic Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D004656:Enalapril; D002945:Cisplatin
keywords: Enalapril; MAPKs; PARP; apoptosis; cisplatin; nephrotoxicity