Renal injury in relation to obesity and the additive effect of hypertension in female and male obese and lean ZSF1 rats

Abstract

Heart failure with preserved ejection fraction (HFpEF) is characterized by obesity, hypertension, diabetes mellitus, and chronic kidney disease. Obese ZSF1 rats, a model of HFpEF, exhibit multiple such comorbidities that can disturb cardiac function. Little attention has been paid to how these comorbidities affect renal disease in ZSF1 rats. HFpEF is found predominantly in women in whom obesity and hypertension are particularly prevalent. Therefore, we characterized the renal phenotype in female and male lean and obese ZSF1 rats and investigated additional effects of worsened hypertension on disease severity. Systolic blood pressure and renal function were assessed biweekly from 12 to 26 wk. From 19 wk, rats were implanted with either a deoxycorticosterone acetate pellet and fed a high-salt diet (DS) or a placebo pellet and fed a normal-salt diet. At 26 wk of age, terminal glomerular filtration rate was assessed via inulin clearance under isoflurane. Renal sections were processed for histological analysis. Lean and obese ZSF1 rats, both female and male, were mildly hypertensive (systolic blood pressure: 140–150 mmHg). All obese ZSF1 rats showed HFpEF. In female normoglycemic ZSF1 rats, obesity associated with mild proteinuria, decreased glomerular filtration rate, and glomerular hypertrophy. DS-worsened hypertension enhanced proteinuria and triggered glomerulosclerosis. Male obese ZSF1 rats were hyperglycemic and showed proteinuria, glomerular hypertrophy and sclerosis, and tubulointerstitial damage. DS-worsened hypertension aggravated this phenotype in male ZSF1 rats. In conclusion, female obese ZSF1 rats develop mild renal dysfunction and DS-worsened hypertension compromises renal function and structure in normoglycemic female obese ZSF1 rats as in hyperglycemic male obese ZSF1 rats.