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.

Distinct Endothelial Cell Responses in the Heart and Kidney Microvasculature Characterize the Progression of Heart Failure With Preserved Ejection Fraction in the Obese ZSF1 Rat With Cardiorenal Metabolic Syndrome

“…9 The ZSF1 strain also autonomously develops renal disease, making it suitable for studying CKD in relation to metabolic triggers. 10,11 HFpEF development in ZSF1 Ob rats was characterized by progressive left ventricle (LV) diastolic dysfunction, concentric LV remodelling, and hypertrophy. 12 This was preceded by insulin resistance, glycosuria, and proteinuria.…”

“…18 On the basis of these combined data, we therefore propose ZSF1 Ob as a small animal model for metabolic syndrome-induced CRS (and thus CRMS), in which the combined metabolic risk factors act together to trigger early onset and progression of CKD and HF, creating the downward spiral of disease progression that is so typical for patients with chronic CRS. 10 …”

Dual A1/A2B Receptor Blockade Improves Cardiac and Renal Outcomes in a Rat Model of Heart Failure with Preserved Ejection Fraction

“…After 24 weeks of treatment, each rat was anesthetized with pentobarbital (45 mg/kg, i.p.) and instrumented for measurements of blood pressure, heart function, renal hemodynamics, and kidney function, as described previously (Tofovic et al, 2007;Bilan et al, 2011). In brief, a PE-240 polyethylene catheter (Becton, Dickinson and Company, Franklin Lakes, NJ) was inserted into the trachea to facilitate breathing.…”

“…BG9928 is a high-affinity A 1 receptor antagonist that also blocks A 2B receptors (Kiesman et al, 2006), and obese ZSF 1 rats are genetically disposed to develop HFpEF, chronic renal insufficiency, vascular endothelial dysfunction, hypertension, hypertriglyceridemia, hypercholesterolemia, hyperglycemia, and insulin resistance (Tofovic and Jackson, 2003;Bilan et al, 2011;Hamdani et al, 2013;Leite et al, 2015a,b).…”

Characterization of liver changes in ZSF1 rats, an animal model of metabolic syndrome

“…These animals are generated by crossing non-hypertensive lean female Zucker diabetic fatty rats (ZDF, +/fa) with lean spontaneously hypertensive HF prone male rats (SHHF/Mcc, +/facp), which share a common genetic background with Wistar Kyoto rats (used as control) and derive from spontaneously multifactorial hypertensive rats. Both lean and obese ZSF1 animals inherit a hypertensive gene from the spontaneously hypertensive rat strain and have high blood pressure (23)(24)(25)(26). With regard to metabolism, ZSF1 animals develop obesity, abdominal adiposity, insulin resistance, oral glucose intolerance, hyperglycaemia and glycosuria, consistent with a type II diabetes mellitus phenotype (27).…”