Abstract P139: Dual Angiotensin Receptor and Neprilysin Inhibition Improves Renal Hemodynamics and Reduces Kidney Damage in Diabetic Rats

Abstract

Dual blockade with an Angiotensin Receptor/Neprilysin Inhibitor (ARNI) reduces proteinuria and glomerulosclerosis in diabetic TGR(mREN2)27 rats (i.e., rats displaying angiotensin II-dependent hypertension) more strongly than single AR blockade (ARB), despite a similar effect on blood pressure. Here we investigated whether this is due to improved renal hemodynamics and/or suppression of renal inflammation. TGR(mREN2)27 rats were made diabetic with streptozotocin for 12 weeks, and treated with placebo (n=10), valsartan (ARB; n=8) or valsartan/sacubitril (ARNI; n=8) from week 9-12. Blood pressure was measured by telemetry. Effective renal plasma flow (eRPF) and glomerular filtration rate (GFR) were assessed by quantifying para-aminohippuric acid and inulin clearances. Renal inflammation was quantified by qPCR (CD68 and CD3ε expression, representative for macrophages and T cells, respectively) and fluorescent activated cell sorting (FACS) analysis. ARNI and ARB lowered blood pressure identically, while only ARNI reduced albuminuria. Severe, chronic ischemia and globally sclerotic glomeruli occurred less frequently in kidneys of ARNI-treated animals vs. ARB-treated animals and controls. ARNI, but not ARB, increased eRPF, and a similar trend was observed for GFR. No treatment affected filtration fraction. ARNI decreased CD68 mRNA expression in both renal cortex and medulla, while ARB increased CD68 as well as CD3ε expression in renal medulla. FACS analysis revealed no differences between the treatment groups in the immune-cell fractions that had infiltrated the kidney. In conclusion, improved renal hemodynamics, combined with reduced macrophage infiltration, may underlie the stronger beneficial effects of ARNI on albuminuria and renal histology in diabetic TGR(mREN2)27 rats versus ARB.