A prophylactic concept should be applied in cases of drug induced and conditions causing acute kidney injury which is a serious and common danger. Epidemiological studies concluded that smoking is an important remediable risk factor for development of acute and chronic kidney disease to end-stage renal disease. High-dose therapy with cisplatin which is a potent antitumor drug is limited by its cumulative nephrotoxicity and neurotoxicity. Exhaustive exercise or overload training causes histological changes in kidney cell manifesting as hematuria, proteinuria and acute renal failure. Exendin-4 (GLP-1 analogue) treatment effectively protected the kidney from injury in a rodent model of renal ischemia reperfusion injury through the suppression of inflammatory reaction, apoptosis and oxidative stress. The aim of this research is to clarify the protective effects of Exendin-4 on different causes of acute kidney injury of experimental animals and compare the injurious effect of nicotine, cisplatin and exhaustive exercise. Design: 70 healthy adult male albino rats were used to study the protective effect of Exendin-4 (administered at a dose of 25 nmol/kg in saline for 11 days) against injurious effect of nicotine bitartrate (at a dose of 200 μg/ml in a 2% saccharine solution as drinking source for 4 weeks), cisplatin (a single intraperitoneal injection at a dose of 7 mg/kg body weight) and exhaustive exercise for 4 weeks. Kidney injury was assessed by analysis of creatinine, BUN, serum KIM and urinary KIM. Results: The results of this study showed that in group IIb (Nicotine/Exendin-4 treated group) and group IVb (Exhaustive exercise/Exendin-4 treated group), the mean values were found to be significantly decreased when compared with non exendin treated groups. On comparing group IIIa (Cisplatin treated group) with that of both group IIa (Nicotine treated group) and group IVa (Exhaustive exercise group), it was found that the mean values were found to be significantly increased for all parameters. However, in group IIIb (Cisplatin/Exendin-4 treated group), the mean values were found to be non-significant for all test parameters when compared with that of group IIIa (Cisplatin treated group). Conclusion: It was observed that exendin-4 has a protective effect against kidney injury induced by nicotine and exhaustive exercise but not against cisplatin.