Pharmacological Research 90 (2014) 36–47 Contents lists available at ScienceDirect Pharmacological Research j ourna l h o mepa ge: www.elsevier.com/l ocate/yphrs Fenofibrate and dipyridamole treatments in low-doses either alone or in combination blunted the development of nephropathy in diabetic rats Pitchai Balakumar a,∗ , Rajavel Varatharajan a , Ying Hui Nyo a , Raja Renushia a , Devarajan Raaginey a , Ann Nah Oh a , Shaikh Sohrab Akhtar a , Mani Rupeshkumar a , Karupiah Sundram b , Sokkalingam A. Dhanaraj c a Pharmacology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Malaysia b Pharmaceutical Chemistry Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Malaysia c Pharmaceutical Technology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Malaysia a r t i c l e i n f o Article history: Received 20 June 2014 Received in revised form 20 August 2014 Accepted 26 August 2014 Available online 27 September 2014 Keywords: Diabetes mellitus Low-dose fenofibrate Low-dose dipyridamole Lipid alteration Uric acid elevation Nephropathy a b s t r a c t Low-doses of fenofibrate and dipyridamole have pleiotropic renoprotective actions in diabetic rats. This study investigated their combined effect relative to their individual treatments and lisinopril in rats with diabetic nephropathy. Streptozotocin (55 mg/kg, i.p., once)-administered diabetic rats were allowed for 10 weeks to develop nephropathy. Diabetic rats after 10 weeks developed nephropathy with discernible renal structural and functional changes as assessed in terms of increase in kidney weight to body weight ratio (KW/BW), and elevations of serum creatinine, urea and uric acid, which accompanied with elevated serum triglycerides and decreased high-density lipoproteins. Hematoxylin–eosin, periodic acid Schiff and Masson trichrome staining confirmed renal pathological changes in diabetic rats that included glomeru- lar capsular wall distortion, mesangial cell expansion, glomerular microvascular condensation, tubular damage and degeneration and fibrosis. Low-dose fenofibrate (30 mg/kg, p.o., 4 weeks) and low-dose dipyridamole (20 mg/kg, p.o., 4 weeks) treatment either alone or in combination considerably reduced renal structural and functional abnormalities in diabetic rats, but without affecting the elevated glucose level. Fenofibrate, but not dipyridamole, significantly prevented the lipid alteration and importantly the uric acid elevation in diabetic rats. Lisinopril (5 mg/kg, p.o., 4 weeks, reference compound), prevented the hyperglycemia, lipid alteration and development of diabetic nephropathy. Lipid alteration and uric acid elevation, besides hyperglycemia, could play key roles in the development of nephropathy. Low- doses of fenofibrate and dipyridamole treatment either alone or in combination markedly prevented the diabetes-induced nephropathy. Their combination was as effective as to their individual treatment, but not superior in preventing the development of diabetic nephropathy. © 2014 Elsevier Ltd. All rights reserved. Introduction Diabetes mellitus is a greatly challenging disease of the 21 cen- tury while the prevalence and mortality rate due to this insidious disease continuously upsurge worldwide. Diabetes mellitus is a group of metabolic disorders, resulting in various microvascular and macrovascular complications [1,2]. The chronic and uncon- trolled diabetes mellitus may affront with several undesirable ∗ Corresponding author at: Pharmacology Unit, Faculty of Pharmacy, AIMST Uni- versity, Semeling, 08100 Bedong, Kedah Darul Aman, Malaysia. Tel.: +60 44298000x1280. E-mail address: pbala2006@gmail.com (P. Balakumar). complications, including diabetic nephropathy, which is associated with reduced glomerular filtration rate, and elevated serum levels of creatinine, and urea [3–5]. In addition, recent evidences implicate uric acid as a mediator of diabetic nephropathy [6]. Diabetic nephropathy is one of leading causes of morbidity and mortality [7]. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II-type 1 (AT 1 ) receptor blockers are employed for the clinical management of diabetic nephropathy [8–10]. However, we still have a dearth of promising pharmacological interven- tions that could satisfactorily improve the clinical outcomes of patients afflicted with diabetic nephropathy. Current treatment protocol for the management of diabetic nephropathy targets to resist glucose and blood pressure elevation. In addition, dyslipid- emia plays an indispensable role in the induction and progression http://dx.doi.org/10.1016/j.phrs.2014.08.008 1043-6618/© 2014 Elsevier Ltd. All rights reserved.