#5907 RENAL INJURY IN RELATION TO OBESITY AND THE ADDITIVE EFFECT OF HYPERTENSION IN FEMALE AND MALE OBESE AND LEAN ZSF1 RATS

Abstract

Abstract Background and Aims Chronic kidney disease co-exists with heart failure with preserved ejection fraction (HFpEF), which is characterized by the presence of obesity, hypertension, and diabetes mellitus type 2. Obese ZSF1 rats, a model of HFpEF, exhibit multiple of these comorbidities that can disturb cardiac function. Little attention has been paid to how these comorbidities affect renal disease in the ZSF1 rats. HFpEF is found predominantly in women in whom obesity and hypertension are particularly prevalent. Therefore, we aimed to characterize the renal phenotype in female and male, lean and obese, ZSF1 rats and investigated additional effects of worsened hypertension on disease severity. Method Systolic blood pressure and renal function were assessed biweekly in female and male, lean and obese, ZSF1 rats from 12 to 26 weeks of age by tail-cuff plethysmography, urine collection via metabolic cages and plasma collection, respectively. From 19 weeks of age, rats were implanted with either a deoxycorticosterone acetate pellet (DOCA) and fed high salt diet (6% NaCl) or with a placebo pellet and fed a normal salt diet. At 26 weeks of age, terminal GFR was assessed via inulin clearance under isoflurane. Renal sections were processed for histological analysis. Results Lean and obese placebo ZSF1 rats, both female and male, were mildly hypertensive (systolic blood pressure 140-150 mmHg). All obese rats showed HFpEF, evidenced by elevated E/e’ ratio. In female normoglycemic ZSF1 rats, obesity associates with mild proteinuria, decreased GFR and glomerular hypertrophy. The addition of DOCA-salt worsened hypertension in female obese ZSF1 rats, but not in their lean counterparts. DOCA-salt-worsened hypertension enhanced proteinuria and triggered glomerulosclerosis in female obese rats. Male obese placebo ZSF1 rats were hyperglycemic and showed proteinuria, glomerular hypertrophy and sclerosis, and tubulo-interstitial damage. DOCA-salt worsened hypertension in both male lean and obese rats and further aggravated proteinuria, tubulo-interstitial damage, glomerular hypertrophy and sclerosis in obese male rats. No effect of DOCA-salt was observed on GFR in both male and female ZSF1 rats. Conclusion Female obese ZSF1 rats developed mild renal disease and DOCA-salt-worsened hypertension deteriorated renal function and structure in normoglycemic female obese ZSF1 rats similar to hyperglycemic male obese ZSF1 rats.