Pulmonary, gastrointestinal and urogenital pharmacology Pioglitazone, a PPARγ agonist, provides comparable protection to angiotensin converting enzyme inhibitor ramipril against adriamycin nephropathy in rat Peter Ochodnicky a,n , Lucia Mesarosova a , Hana Cernecka a , Jan Klimas a , Peter Krenek a , Maaike Goris b , Richard P.E. van Dokkum b , Robert H. Henning b , Jan Kyselovic a a Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University Bratislava, Slovak Republic b Department of Clinical Pharmacology, University Medical Center Groningen (UMCG) and Groningen Institute for Drug Exploration (GUIDE), University of Groningen, The Netherlands article info Article history: Received 8 August 2013 Received in revised form 18 February 2014 Accepted 20 February 2014 Available online 28 February 2014 Keywords: PPARγ agonists ACE inhibitors Adriamycin nephropathy Chronic kidney disease Renin–angiotensin system Pioglitazone abstract Peroxisome proliferator-activated receptor γ (PPARγ) agonists have been shown to ameliorate diabetic nephropathy, but much less are known about their effects in non-diabetic nephropathies. In the present study, metabolic parameters, blood pressure, aortic endothelial function along with molecular and structural markers of glomerular and tubulointerstitial renal damage, were studied in a rat model of normotensive nephropathy induced by adriamycin and treated with PPARγ agonist pioglitazone (12 mg/kg, po), angiotensin converting enzyme (ACE) inhibitor ramipril (1 mg/kg, po) or their combination. Pioglitazone had no effect on systolic blood pressure, marginally reduced glycemia and improved aortic endothelium-dependent relaxa- tion. In the kidney, pioglitazone prevented the development of proteinuria and focal glomerulosclerosis to the similar extent as blood-pressure lowering ramipril. Renoprotection provided by either treatment was associated with a reduction in the cortical expression of profibrotic plasminogen activator inhibitor-1 and microvascular damage-inducing endothelin-1, and a limitation of interstitial macrophage influx. Treatment with PPARγ agonist, as well as ACE inhibitor comparably affected renal expression of the renin–angiotensin system (RAS) components, normalizing increased renal expression of ACE and enhancing the expression of Mas receptor. Interestingly, combined pioglitazone and ramipril treatment did not provide any additional renoprotection. These results demonstrate that in a nondiabetic renal disease, such as adriamycin-induced nephropathy, PPARγ agonist pioglitazone provides renoprotection to a similar extent as an ACE inhibitor by interfering with the expression of local RAS components and attenuating related profibrotic and inflamma- tory mechanisms. The combination of the both agents, however, does not lead to any additional renal benefit. & 2014 Elsevier B.V. All rights reserved. 1. Introduction In the last decade, targeting the peroxisome proliferator-activated receptor γ (PPARγ) has become a viable strategy to correct metabolic abnormalities associated with insulin resistance in type II diabetic and metabolic syndrome patients. Thiazolidinediones, PPARγ agonists including pioglitazone, exert a complex systemic metabolic response leading to enhanced insulin sensitivity in peripheral tissues primarily by affecting the transcription of genes governing metabolic and endocrine activity of adipose tissue (Yki-Jarvinen, 2004). However, PPARγ receptors, serving as nuclear ligand-activated transcription factors, are also expressed in other cell types including macrophages and various epithelial and muscle(-like) cells (Guan and Breyer, 2001; Willson et al., 2001). Consequently, the spectrum of PPARγ-regulated genes may include those involved in inflammation, proliferation/ apoptosis, fibrosis and vascular reactivity (Schiffrin, 2005; Willson et al., 2001), possibly contributing to the general cardiovascular and end-organ protection of systemic PPARγ activation. Based on the assumption of systemic metabolic benefits, PPARγ agonists have been shown to ameliorate diabetic nephropathy in several animal models (Baylis et al., 2003; Ko et al., 2008) and human studies (Agarwal et al., 2005; Sarafidis et al., 2005). Although glycemic and lipid control may contribute to the renoprotection, several lines of evidence suggest that activation of PPARγ expressed in the kidney itself (e.g. in podocytes, tubular epithelium or microvasculature (Guan et al., 2001; Guan and Breyer, 2001)) provides additional renal benefit in diabetic nephropathy by reducing mesangial extracellular matrix production, maintaining podocyte number and function, and limiting interstitial infiltration of monocytes/macrophages (Isshiki et al., 2000; Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/ejphar European Journal of Pharmacology http://dx.doi.org/10.1016/j.ejphar.2014.02.023 0014-2999 & 2014 Elsevier B.V. All rights reserved. n Correspondence to: Department of Pathology, Academic Medical Center, Uni- versity of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. Tel.: þ31 205665645; fax: þ31 205669523. E-mail address: p.ochodnicky@amc.uva.nl (P. Ochodnicky). European Journal of Pharmacology 730 (2014) 51–60