SAT-179 RAS, SEH AND ETA BLOCKADE IN THE COURSE OF CHRONIC KIDNEY DISEASE IN 5/6 NEPHRECTOMIZED REN-2 TRANSGENIC RATS

Abstract

Previous studies in Ren-2 transgenic hypertensive rats (TGR) after 5/6 renal ablation (5/6 NX) have shown that besides pharmacological blockade of the renin-angiotensin system (RAS) also increasing kidney tissue epoxyeicosatrienoic acids (EET) levels by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for degradation of EETs, and endothelin type A (ETA) receptor blockade, retards chronic kidney disease (CKD) progression. Heterozygous TGR and age-matched Hannover-Sprague Dawley (HanSD) normotensive controls were used. Trandolapril and losartan were used as RAS blockade, cis-4-[4-(3-adamantan-1-yl-ureido)cyclohexyloxy]benzoic acid (c-AUCB) as sEH blockade and atrasentan as ETA receptor blockade, administered in drinking water. 5/6 nephrectomy was done at the age of 6 weeks and 6 weeks later the appropriate treatment was started. Animals were treated with RAS blockade, a combination of RAS and sEH blockade, or a combination of RAS, sEH and ETA blockade. Survival rate, albuminuria, clearance of endogenous creatinine, glomerular damage (glomerulosclerosis index), and renal cortical tubulointerstitial injury were assessed. The addition of sEH inhibition to RAS blockade improved survival rate, further reduced albuminuria and renal glomerular and kidney tubulointerstitial injury, and attenuated the decline in creatinine clearance – all this as compared with 5/6 NX TGR treated with RAS blockade alone. Addition of ETA receptor antagonist to the combined RAS and sEH blockade not only offered no additional renoprotection but, surprisingly, abolished the beneficial effects of adding sEH inhibitor to the RAS blockade. These data indicate that pharmacological strategies that combine the blockade of RAS and sEH could be a novel tool to combat the progression of CKD. Any attempts to add additional substances to this therapeutic regime should be made with extreme caution.