Dose‐dependent effects of losartan and salt‐sensitivity of diabetic nephropathy in ZSF1 rats

Abstract

Diabetic nephropathy (DN) is the leading cause of end stage renal disease. Renal complications of diabetes are influenced by hypertensive comorbidity while angiotensin receptor blockade (ARB) represents current standard of care. We hypothesized that high salt (HS) intake would exacerbate, and ARB by losartan (LOS) would attenuate progression of DN. Male obese ZSF1 (OB‐ZSF1) rats (8 wk) underwent unilateral nephrectomy, and received (po, qd for 15 wks) vehicle (VEH), LOS (3, 10, or 30 mg/kg), or 0.9% NaCl water. Male lean ZSF1 (CON) served as controls. Blood pressure data, urine and blood samples were collected every 4 weeks. Metabolic data support progression of diabetes in OB‐ZSF1. LOS attenuated while HS exacerbated arterial hypertension indicating salt‐sensitivity in OB‐ZSF1. Albuminuria was time‐dependently increased, dose‐dependently inhibited by LOS and exacerbated by HS by 18 wks of age. Endpoint renal injury urinary biomarkers Kim‐1 and osteopontin were increased (6‐, 40‐fold, respectively) in VEH relative to CON, while LOS inhibited their excretion. HS dramatically further increased urinary Kim‐1 and osteopontin excretion (~3‐fold each) relative to VEH. LOS improved, while HS worsened glomerular filtration rate and renal plasma flow relative to VEH as directly evaluated at endpoint. We conclude LOS effectively attenuates progression and severity of DN, while HS increases renal injury in OB‐ZSF1.