RENAL FUNCTION AND STRUCTURE IN DIABETIC, HYPERTENSIVE, OBESE ZDFxSHHF-HYBRID RATS

Abstract

The obese ZDFxSHHF-fa/fa(cp) model was developed by crossing lean female Zucker Diabetic Fatty (ZDF +/fa) and lean male Spontaneously Hypertensive Heart Failure (SHHF/Mcc-fa(cp), +/fa) rats. The purpose of the present study was to determine renal function and morphology, hemodynamics, and metabolic status in ZDFxSHHF rats. Two sets of experiments were conducted. First, we evaluated heart and kidney function and metabolic status in aged (46 weeks old) male obese ZDFxSHHF and age matched obese SHHF rats, lean Spontaneously Hypertensive (SHR) and lean normotensive Wistar Kyoto (WKY) rats. In the second set of experiments, renal function and structure as well as metabolic and lipid status were determined in lean (LN) and obese (OB) adult (29-weeks of age) ZDFxSHHF rats. At 46 weeks of age ZDFxSHHF rats are hypertensive expressing marked cardiac hypertrophy associated with diastolic dysfunction and preserved contractile function. Fasted hyperglycemia and hyperinsulinemia are accompanied by moderate hypercholesterolemia and hypertriglyceridemia. Obese aged ZDFxSHHF have marked renal hypertrophy, a 3-8 fold decrease in creatinine clearance (compared with SHHF, SHR and WKY), a high percent of segmental + global glomerulosclerosis (59.8%+/-10.8), and severe tubulointerstitial and vascular changes. Obese ZDFxSHHF rats die at an early age (approximately 12 months) from end-stage renal failure. Studies conducted in 29-week animals showed that, although both LN and OB 29-week old animals are hypertensive, OB animals have more severely compromised renal function and structure as compared with lean litter-mates (kidney weight: 2.56+/-0.16 vs. 1.61+/-0.12 g; creatinine clearance: 0.42+/-0.04 vs. 1.24+/-0.13 L/g kid/day; renal vascular resistance 12.39+/-1.4 vs. 6.14+/-0.42 mmHg/mL/min/g kid; protein excretion: 556+/-16 vs. 159+/-9mg/day/g kid, p < 0.05, OB vs. LN, respectively). Obesity is also associated with hyperglycemia (424+/-37 vs. 115+/-11 mg/dL), hyperinsulinemia (117.2+/-8.8 vs. 42.3+/-3.5 microU/mL), hypertriglyceridemia (5200+/-702 vs. 194+/-23 mg/dL), hypercholesterolemia (632+/-39 vs. 109+/-4mg/dL), and presence of segmental + global glomerulosclerosis (20.1+/-3.2% vs. 0.1+/-0.1%) with prominent tubular and interstitial changes (p < 0.05, OB vs. LN, respectively). In summary, the present study indicates that the crossing of rat strains of nephropathy produces hybrids that carry a high risk for severe renal dysfunction. The ZDFxSHHF rats express insulin resistance, hypertension, dislipidemia and obesity and develop severe renal dysfunction. In addition, the hybrids do not develop some of the complications (hydronephrosis or congestive heart failure) common for the parental strains that may compromise studies of renal function and structure. Therefore, the ZDFxSHHF rat may be a useful model fore valuating risk factors and pharmacological interventions in chronic renal failure.

Diabetic nephropathy and long-term treatment effects of rosiglitazone and enalapril in obese ZSF1 rats

“…Similarly, we demonstrated 10-to 25-fold increase in proteinuria with significant mesangial expansion and tubulointerstitial fibrosis in animals older than 40 weeks (Tofovic et al 2000, Zhang et al 2007) and doubling of glomerular basement membrane thickness by 20 weeks of age in obese ZSF1 rats has been reported (Prabhakar et al 2007). Recently, a combined classification for human type-1 and type-2 DN was developed that includes four hierarchical categories of glomerular lesions with separate evaluation for degrees of interstitial and vascular involvement (Tervaert et al 2010); according to these criteria, 20-to 44-week-old obese ZSF1 rats develop class II glomerular lesions characterized by basement membrane thickening and mesangial expansion with mild to moderate (5-30%) glomerulosclerosis (Tofovic et al 2000, Griffin et al 2007, Prabhakar et al 2007, Zhang et al 2007, Rafikova et al 2008, Joshi et al 2009). Importantly, our previous studies indicate that by 50 weeks of age, male obese ZSF1 rats had O50% glomerulosclerosis (Tofovic et al 2000.…”

“…Both lean and obese animals inherit the gene for hypertension from the SHR strain and have similarly elevated blood pressure, but only obese ZSF1 rats (fa/fa cp ) develop dyslipidemia, hyperglycemia, and renal sclerosis and fibrosis (Tofovic et al 2000, Zhang et al 2007, Rafikova et al 2008. Recently, Griffin et al (2007) demonstrated that the development of kidney disease in the ZSF1 rat model is largely independent of hypertension and/or its potential renal transmission.…”

Diabetic Nephropathy Is Associated with Oxidative Stress and Decreased Renal Nitric Oxide Production

“…Together with severe hyperglycemia, the renal disease mimicked nephropathy of type 2 diabetes in humans. Although originally described by Tefovic et al 2 and additional literature published recently, 3 the characterization of renal disease in ZSF 1 rats remains far from complete. The presence of severe hyperlipidemia, especially hypertriglyceridemia, is particularly noteworthy because this degree of hyperlipidemia is not typical of human DN.…”

“…These rats turn obese shortly after birth and develop diabetes (8 wk), renal disease with proteinuria, and renal failure by 20 wk, with severe renal failure and nephrosis by 46 wk, and die with end-stage renal failure at the age of 12 mo. 2 Unlike the parental SHHF strain, ZSF 1 rats do not develop congestive heart failure 31 ; therefore, the ZSF 1 rats (Charles River Laboratories, Indianapolis, IN) constitute the currently best available model to study renal disease in type 2 diabetes. Only male ZSF 1 rats were used for this study.…”

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).…”