Evaluating the drug repurposing benefits of clopidogrel against adenine induced chronic renal failure in experimental animals

Abstract

Introduction: Chronic renal failure (CRF) is a life-threatening condition which can be defined as a progressive and irreversible loss of renal function associated with inflammation and oxidative stress having limited treatment options. The anti-platelet drug, clopidogrel showed nephroprotective action in 5/6 nephrectomy model, lithium induced nephrogenic diabetes insipidus and diabetes-induced renal fibrosis. Objectives: In this study we evaluated the effect of clopidogrel on various serum, urine parameters linked with CRF, vascular calcification, electrolyte abnormalities, inflammatory markers and renal histology. Materials and Methods: Seven groups of male Wistar rats were treated with saline normal control), adenine (50 mg/kg, disease control), clopidogrel (15, 30, 60 mg/kg) concomitantly with adenine (preventive regimen), clopidogrel 60 mg/kg from day 15th curative regimen) and acetylcysteine (50 mg/kg) in combination with taurine as standard drug (50 mg/kg) from day 15th in a 4-week model. Following the completion of the treatments, urine, blood, and kidneys were collected from all rats, and then various biochemical, oxidative, and histological parameters were estimated. Results: Adenine administration decreased body weight and kidney function due to injury as indicated by increased markers like serum urea, uric acid, creatinine and potassium in all animals except normal control group. There was a significant difference between disease and test drug groups especially for 60 mg/kg of preventive and curative regimen for all the estimated parameters. Adenine administration caused histopathological alterations, significant reduction in antioxidant indices and initiated a fibrotic response in kidney by increasing the profibrotic protein like transforming growth factor-beta (TGF-β1). Conclusion: The results suggest that clopidogrel treatment improves majority of the parameters in a dose-dependent manner and the renoprotective effect might be associated with its antioxidant and anti- fibrosis activity.