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

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

doi:10.3389/fphys.2019.01145

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

Front Physiol. 2019 Sep 18:10:1145. doi: 10.3389/fphys.2019.01145. eCollection 2019.

Authors

Ivana Vaněčková¹, Silvie Hojná¹, Zdenka Vernerová², Michaela Kadlecová¹, Hana Rauchová¹, Elzbieta Kompanowska-Jezierska³, Zdeňka Vaňourková⁴, Luděk Červenka⁴, Josef Zicha¹

Affiliations

¹ Department of Experimental Hypertension, Institute of Physiology, Czech Academy of Sciences, Prague, Czechia.
² Department of Pathology, Third Faculty of Medicine, Charles University, Prague, Czechia.
³ Department of Renal and Body Fluid Physiology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.
⁴ Institute for Clinical and Experimental Medicine, Prague, Czechia.

Abstract

Objective: Our previous study in heterozygous Ren-2 transgenic rats (TGR) demonstrated that long-term treatment with endothelin receptor A (ET_A) 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 ET_A blockade is known to cause edema, we were interested whether diuretic treatment added to this therapy would be beneficial.

Design and methods: Partial 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 ET_A receptor blockade (atrasentan), or (iii) diuretic (hydrochlorothiazide) added to the combined RAS + ET_A blockade for 50 weeks following NX.

Results: At the end of the study systolic blood pressure and cardiac hypertrophy were similarly decreased in all treated groups. Survival was significantly improved by ET_A receptor blockade added to RAS blockade with no further effects of diuretic treatment. However, additional diuretic treatment combined with RAS + ET_A 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 ET_A blockade. In rats treated with additional diuretic, proteinuria was progressively reduced throughout the experiment.

Conclusion: A diuretic added to the combined RAS and ET_A 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).

Keywords: atrasentan; chronic kidney disease; hydrochlorothiazide; losartan; nephrectomy; renoprotection; trandolapril.