Renal function and structure in diabetic, hypertensive, obese ZDFxSHHF-hybrid rats

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 (similar to 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 littermates (kidney weight: 2.56 +/- 0.16 vs. 1.61 +/- 0.12g; 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 +/- 9 mg/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 mu U/mL), hypertriglyceridemia (5200 +/- 702 vs. 194 +/- 23 mg/dL), hypercholesterolemia (632 +/- 39 vs. 109 +/- 4 mg/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.