title: Diabetic nephropathy and long-term treatment effects of rosiglitazone and enalapril in obese ZSF1 rats.
abstract: Diabetic nephropathy (DN) is a major cause of end-stage renal disease. Yet the pathogenic mechanisms underlying the development of DN are not fully defined, partially due to lack of suitable models that mimic the complex pathogenesis of renal disease in diabetic patients. In this study, we describe early and late renal manifestations of DN and renal responses to long-term treatments with rosiglitazone or high-dose enalapril in ZSF1 rats, a model of metabolic syndrome, diabetes, and chronic renal disease. At 8 weeks of age, obese ZSF1 rats developed metabolic syndrome and diabetes (hyperglycemia, glucosuria, hyperlipidemia, and hypertension) and early signs of renal disease (proteinuria, glomerular collagen IV deposition, tubulointerstitial inflammation, and renal hypertrophy). By 32 weeks of age, animals developed renal histopathology consistent with DN, including mesangial expansion, glomerulosclerosis, tubulointerstitial inflammation and fibrosis, tubular dilation and atrophy, and arteriolar thickening. Rosiglitazone markedly increased body weight but reduced food intake, improved glucose control, and attenuated hyperlipidemia and liver and kidney injury. In contrast, rosiglitazone markedly increased cardiac hypertrophy via a blood pressure-independent mechanism. High-dose enalapril did not improve glucose homeostasis, but normalized blood pressure, and nearly prevented diabetic renal injury. The ZSF1 model thus detects the clinical observations seen with rosiglitazone and enalapril in terms of primary and secondary endpoints of cardiac and renal effects. This and previous reports indicate that the obese ZSF1 rat meets currently accepted criteria for progressive experimental diabetic renal disease in rodents, suggesting that this may be the best available rat model for simulation of human DN.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Vascular Medicine Institute, Departments of Medicine Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA.
authors.forename: Victor P
authors.initials: VP
authors.lastname: Bilan
authors.forename: Eman M
authors.initials: EM
authors.lastname: Salah
authors.forename: Sheldon
authors.initials: S
authors.lastname: Bastacky
authors.forename: Huw B
authors.initials: HB
authors.lastname: Jones
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Mayers
authors.forename: Bradley
authors.initials: B
authors.lastname: Zinker
authors.forename: Simon M
authors.initials: SM
authors.lastname: Poucher
authors.forename: Stevan P
authors.initials: SP
authors.lastname: Tofovic
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D004195:Disease Models, Animal; D004656:Enalapril / Q000627:therapeutic use*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008099:Liver / Q000473:pathology; D008297:Male; D024821:Metabolic Syndrome / Q000209:etiology / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology; D009765:Obesity / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D047495:PPAR gamma / Q000819:agonists; D051381:Rats; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D004656:Enalapril