title: Pioglitazone, a PPARγ agonist, provides comparable protection to angiotensin converting enzyme inhibitor ramipril against adriamycin nephropathy in rat.
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 (12mg/kg, po), angiotensin converting enzyme (ACE) inhibitor ramipril (1mg/kg, po) or their combination. Pioglitazone had no effect on systolic blood pressure, marginally reduced glycemia and improved aortic endothelium-dependent relaxation. 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 inflammatory mechanisms. The combination of the both agents, however, does not lead to any additional renal benefit.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University Bratislava, Slovak Republic. Electronic address: p.ochodnicky@amc.uva.nl.
authors.forename: Peter
authors.initials: P
authors.lastname: Ochodnicky
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University Bratislava, Slovak Republic.
authors.forename: Lucia
authors.initials: L
authors.lastname: Mesarosova
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University Bratislava, Slovak Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Cernecka
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University Bratislava, Slovak Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Klimas
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University Bratislava, Slovak Republic.
authors.forename: Peter
authors.initials: P
authors.lastname: Krenek
authors.affiliation: Department of Clinical Pharmacology, University Medical Center Groningen (UMCG) and Groningen Institute for Drug Exploration (GUIDE), University of Groningen, The Netherlands.
authors.forename: Maaike
authors.initials: M
authors.lastname: Goris
authors.affiliation: Department of Clinical Pharmacology, University Medical Center Groningen (UMCG) and Groningen Institute for Drug Exploration (GUIDE), University of Groningen, The Netherlands.
authors.forename: Richard P E
authors.initials: RP
authors.lastname: van Dokkum
authors.affiliation: Department of Clinical Pharmacology, University Medical Center Groningen (UMCG) and Groningen Institute for Drug Exploration (GUIDE), University of Groningen, The Netherlands.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Henning
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University Bratislava, Slovak Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Kyselovic
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects; D018450:Disease Progression; D004317:Doxorubicin / Q000009:adverse effects*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D008297:Male; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D011507:Proteinuria / Q000517:prevention & control; D017257:Ramipril / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000235:genetics; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D047495:PPAR gamma; D045162:Thiazolidinediones; D004317:Doxorubicin; D017257:Ramipril; D000077205:Pioglitazone
keywords: ACE inhibitors; Adriamycin nephropathy; Chronic kidney disease; PPARγ agonists; Pioglitazone; Renin–angiotensin system