Renin–angiotensin system blockade alone or combined with ET_A receptor blockade: effects on the course of chronic kidney disease in 5/6 nephrectomized Ren-2 transgenic hypertensive rats

ABSTRACT

Background: Early addition of endothelin (ET) type A (ET_A) receptor blockade to complex renin–angiotensin system (RAS) blockade has previously been shown to provide better renoprotection against progression of chronic kidney disease (CKD) in Ren-2 transgenic hypertensive rats (TGR) after 5/6 renal ablation (5/6 NX). In this study, we examined if additional protection is provided when ET_A blockade is applied in rats with already developed CKD. Methods: For complex RAS inhibition, an angiotensin-converting enzyme inhibitor along with angiotensin II type 1 receptor blocker was used. Alternatively, ET_A receptor blocker was added to the RAS blockade. The treatments were initiated 6 weeks after 5/6 NX and the follow-up period was 50 weeks. Results: When applied in established CKD, addition of ET_A receptor blockade to the complex RAS blockade brought no further improvement of the survival rate (30% in both groups); surprisingly, aggravated albuminuria (588 ± 47 vs. 245 ± 38 mg/24 h, p < 0.05) did not reduce renal glomerular injury index (1.25 ± 0.29 vs. 1.44 ± 0.26), did not prevent the decrease in creatinine clearance (203 ± 21 vs. 253 ± 17 µl/min/100 g body weight), and did not attenuate cardiac hypertrophy to a greater extent than observed in 5/6 NX TGR treated with complex RAS blockade alone. Conclusions: When applied in the advanced phase of CKD, addition of ET_A receptor blockade to the complex RAS blockade brings no further beneficial renoprotective effects on the CKD progression in 5/6 NX TGR, in addition to those seen with RAS blockade alone.

KEYWORDS:

• Chronic kidney disease
• endothelin system
• hypertension
• renin–angiotensin system
• 5/6 nephrectomy

Conflict of interest statement

None.

Funding

This study was primarily supported by Ministry of Health of the Czech Republic grant no. 15-28671A to V.Č.Ch. All rights reserved. The Center for Experimental Medicine (IKEM) received financial support from the European Commission within the Operational Program Prague–Competitiveness, project “Rozvoj infrastruktury PEM” (No. CZ.2.16/3.1.00/28025). This study was also result of non-commercial cooperation between IKEM and OMNIMEDICUs Inc. and ELLA-CZ Ltd. within this project.

Additional information

Funding

This study was primarily supported by Ministry of Health of the Czech Republic grant no. 15-28671A to V.Č.Ch. All rights reserved. The Center for Experimental Medicine (IKEM) received financial support from the European Commission within the Operational Program Prague–Competitiveness, project “Rozvoj infrastruktury PEM” (No. CZ.2.16/3.1.00/28025). This study was also result of non-commercial cooperation between IKEM and OMNIMEDICUs Inc. and ELLA-CZ Ltd. within this project.