Effects of Combined Endothelin A Receptor and Renin‐Angiotensin System Blockade on The Regression of Chronic Kidney Disease in 5/6 Nephrectomized Ren‐2 Transgenic Rats

Abstract

Study objectiveWe tested the hypothesis where the combined renin‐angiotensin system (RAS) and endothelin 1 (ETA) receptor blockade could be more effective in the slowing of progression of CKD with already established sings of renal injury than antihypertensive treatment based on isolated RAS inhibition in 5/6 nephrectomized (NX) Ren‐2 transgenic hypertensive rats (TGR).MethodsIn five groups of male rats: sham‐operated TGR; untreated 5/6 NX TGR; 5/6 NX TGR with dual RAS blockade (trandolapril 6 mg/L and losartan 100 mg/L); 5/6 NX TGR with combined treatment with RAS and ETA receptor blockade (atrasentan 5 mg/kg/day). 5/6 NX was done in age of 6 weeks and the treatments were initiated 6 weeks after 5/6 NX. Rats were placed into metabolic cages to determine albuminuria at weeks 6, 8, 12, 16, 20, 30. In other groups, concentrations of ANG II and ET1 were evaluated in the kidneys after 2 weeks of treatments.ResultsMortality of untreated 5/6 NX TGR was 100% at 17th week compared to sham‐operated rats with mortality 0% to 30th week. Mortality of 5/6 NX TGR with RAS blockade was 32 % and in group with RAS and ETA receptor blockade 37 % at the end of 30th week. In 5/6 NX TGR, both treatments reduced enhanced albuminuria, plasma and kidney ANG II and cortical ET 1 concentrations similarly.ConclusionThere is no additive effect of combined ETA receptor and RAS blockade on the regression of CKD in 5/6 NX TGR most likely due to efficient reduction of ET 1in the renal cortex by the dual RAS inhibition.