Renoprotection Provided by Additional Diuretic Treatment in Partially Nephrectomized Ren-2 Transgenic Rats Subjected to the Combined RAS and ETA Blockade.

Ivana Vaněčková,Josef Zicha,Elzbieta Kompanowska-Jezierska,Silvie Hojná,Hana Rauchová,Zdeňka Vaňourková,Zdenka Vernerová,Michaela Kadlecová,Luděk Červenka

doi:10.3389/fphys.2019.01145

Abstract

ObjectiveOur previous study in heterozygous Ren-2 transgenic rats (TGR) demonstrated that long-term treatment with endothelin receptor A (ETA) blocker atrasentan added to the renin-angiotensin system (RAS) blockade had renoprotective effects in a model of chronic kidney disease (CKD) induced by partial nephrectomy. Since ETA blockade is known to cause edema, we were interested whether diuretic treatment added to this therapy would be beneficial.Design and MethodsPartial nephrectomy (NX) was performed at the age of 3 months in TGR rats which were subjected to: (i) RAS blockade alone (angiotensin receptor blocker losartan and angiotensin converting enzyme inhibitor trandolapril), (ii) combined RAS (losartan and trandolapril) and ETA receptor blockade (atrasentan), or (iii) diuretic (hydrochlorothiazide) added to the combined RAS + ETA blockade for 50 weeks following NX.ResultsAt the end of the study systolic blood pressure and cardiac hypertrophy were similarly decreased in all treated groups. Survival was significantly improved by ETA receptor blockade added to RAS blockade with no further effects of diuretic treatment. However, additional diuretic treatment combined with RAS + ETA blockade decreased body weight and had beneficial renoprotective effects – reductions of both kidney weight and kidney damage markers. Proteinuria gradually increased in rats treated with RAS blockade alone, while it was substantially lowered by additional ETA blockade. In rats treated with additional diuretic, proteinuria was progressively reduced throughout the experiment.ConclusionA diuretic added to the combined RAS and ETA blockade has late renoprotective effects in CKD induced by partial nephrectomy in Ren-2 transgenic rats. The diuretic improved: renal function (evaluated as proteinuria and creatinine clearance), renal morphology (kidney mass, glomerular volume), and histological markers of kidney damage (glomerulosclerosis index, tubulointerstitial injury).

Highlights

Chronic kidney disease (CKD) is often associated with hypertension, diabetes and obesity
While 80% of the sham-operated TGR survived until the end of the experiment, untreated TGR-NX rats began to die at week 4 and no TGR-NX rat survived 18 weeks following nephrectomy (Figure 1A)
Partial nephrectomy resulted in a substantial reduction of body weight gain in all groups but the treatments used in our experiments enabled a significant, subsequent increase in body weight, the body weight in all treated groups of TGRNX animals was still lower compared to the sham-operated TGR rats (Figure 1B)

Summary

Introduction

Chronic kidney disease (CKD) is often associated with hypertension, diabetes and obesity. Due to its increasing occurrence, it represents an important burden for a healthcare system. As the world population is living longer, the prevalence of CKD increases. The most widely used therapy of CKD, the “gold standard,” is provided by the inhibition of the renin-angiotensin system (RAS) exerting both antihypertensive and nephroprotective effects (Raij, 2005). This therapy is not able to halt the progression of CKD to end-stage renal disease (ESRD) and, new additive/combination therapies are strongly needed (Breyer and Susztak, 2016; Komers and Plotkin, 2016)

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