Protective effects of captopril in diabetic rats exposed to ischemia/reperfusion renal injury Amr A. Fouad a , Abdulruhman S. Al-Mulhim b , Iyad Jresat c and Mohamed A. Morsy d a Department of Biomedical Sciences, Pharmacology Division, College of Medicine, b Department of Surgery, College of Medicine, c Department of Biomedical Sciences, Pathology Division, College of Medicine and d Department of Pharmaceutical Sciences, Pharmacology Division, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Saudi Arabia Keywords captopril; diabetes mellitus; ischaemia/reperfusion; kidney; rats Correspondence Amr A. Fouad, Department of Biomedical Sciences, Pharmacology Division, College of Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia. E-mail: amrfouad65@yahoo.com Received December 15, 2011 Accepted August 5, 2012 doi: 10.1111/j.2042-7158.2012.01585.x Abstract Objectives To investigate the potential protective effects of captopril, the angiotensin-converting enzyme inhibitor, in diabetic rats exposed to ischaemia/ reperfusion (I/R) renal injury. Methods Following successful induction of diabetes, captopril treatment (50 mg/ kg/day, p.o.) was applied for 4 weeks, after which bilateral renal ischaemia was induced for 30 min followed by reperfusion for 24 h. Results Captopril significantly attenuated hyperglycaemia and hypoinsulinaemia in diabetic rats, and significantly reduced the elevations of serum creatinine and aldosterone levels, and renal malondialdehyde, tumour necrosis factor-a and nitric oxide (NO), and prevented the depletion of reduced glutathione caused by I/R in diabetic rats. Histopathological renal tissue damage induced by I/R in dia- betic rats was ameliorated by captopril treatment. Immunohistochemical analysis revealed that captopril significantly attenuated the reduction of insulin content in pancreatic islet b-cells, and decreased the I/R-induced expression of inducible NO synthase, nuclear factor-kB, Fas ligand and caspase-3, and increased the expres- sion of survivin and heme oxygenase-1 in the kidney tissue of diabetic rats. Conclusions Captopril represents a potential candidate to reduce the risk of renal injury induced by ischaemia/reperfusion in type 2 diabetes. Introduction Renal ischaemia/reperfusion (I/R) is a major cause of acute kidney injury, which leads to high morbidity and mortality in clinical practice. Reperfusion of ischaemic renal tissue initiates a complex series of cellular events that eventually lead to necrotic and apoptotic renal cell death. [1] Previous studies revealed increased susceptibility of the kidney to I/R injury in streptozotocin-diabetic rats. [2–4] It was demon- strated that short ischaemia (for 30 min) in non-diabetic rats resulted in reversible acute renal failure, but caused a progressive injury with end-stage renal failure in diabetic rats. [5] Also, it was reported that renal ischaemia produced more severe kidney injury with high risk of failing to show recovery in diabetic patients than in non-diabetic individu- als. [6,7] The mechanisms underlying enhanced vulnerability of the kidney to I/R injury in diabetes are not fully eluci- dated. However, oxidative stress and intense inflammatory reaction in the kidney tissue seem to play a crucial role. [5,8,9] Angiotensin II, the central product of the renin– angiotensin–aldosterone system, induces tissue oxidative stress, inflammation and apoptosis. [10] Captopril, an angiotensin-converting enzyme inhibitor, decreases the cir- culating and tissue levels of angiotensin II. Also, as a thiol- containing compound, captopril possesses powerful antioxidant activity, scavenges different types of reactive oxygen species and prevents lipid peroxidation. [11,12] It was reported that captopril protected against tissue injury induced by oxidative stress and inflammation in various experimental models. [13–15] In addition, previous studies showed that captopril enhanced pancreatic islet blood flow, augmented insulin secretion, improved glycaemic control, and attenuated diabetic nephropathy in animals and humans. [16–19] Therefore, captopril has the potential to protect against I/R renal injury associated with diabetes mellitus. Also, to the best of our knowledge, this is the first And Pharmacology Journal of Pharmacy Research Paper © 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society 2013 Journal of Pharmacy and Pharmacology, 65, pp. 243–252 243