Věra Čertíková Chábová1, Zdenka Vernerová2, Petr Kujal2, Zuzana Husková3, Petra Škaroupková3, Vladimír Tesař1, Herbert J Kramer4, Elzbieta Kompanowska-Jezierska5, Agnieszka Walkowska5, Janusz Sadowski5, Luděk Červenka3, Ivana Vaněčková6. 1. Department of Nephrology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic. 2. Department of Pathology, 3rd Faculty of Medicine, Charles University, Prague, Czech Republic. 3. Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic. 4. Section of Nephrology, Medical Policlinic, Department of Medicine, University of Bonn, Bonn, Germany. 5. Department of Renal and Body Fluid Physiology, M. Mossakowski Medical Research Centre, Polish Academy of Science, Warsaw, Poland. 6. Institute of Physiology v.v.i., Academy of Sciences of the Czech Republic, Prague, Czech Republic. Electronic address: ivanava@biomed.cas.cz.
Abstract
AIMS: There is evidence that in addition to hypertension and hyperactivity of the renin-angiotensin system (RAS), enhanced intrarenal activity of endothelin (ET) system contributes to the pathophysiology and progression of chronic kidney disease (CKD). This prompted us to examine if this progression would be alleviated by addition of type A ET receptor (ETA) blockade to the standard blockade of RAS. MAIN METHODS: Ren-2 transgenic rats (TGR) after 5/6 renal ablation (5/6 NX) served as a model of CKD. For RAS inhibition a combination of angiotensin-converting enzyme inhibitor (trandolapril, 6 mg/L drinking water) and angiotensin II type 1 receptor blocker (losartan, 100 mg/L drinking water) was used. Alternatively, ETA receptor blocker (atrasentan, 5 mg·kg(-1)·day(-1) in drinking water) was added to the combined RAS blockade. The follow-up period was 44 weeks after 5/6 NX, and the rats' survival rate, systolic blood pressure (SBP), proteinuria and indices of renal glomerular damage were evaluated. KEY FINDINGS: The survival rate was at first improved, by either therapeutic regime, however, the efficiency of RAS blockade alone considerably decreased 36 weeks after 5/6 NX: final survival rate of 65% was significantly lower than 91% achieved with combined RAS and ETA receptor blockade. SBP was not affected by the addition of ETA blockade while proteinuria and renal glomerular damage were further reduced. SIGNIFICANCE: Our data show that a combined RAS and ETA receptor blockade exhibits additional beneficial effects on survival rate and the progression of CKD in 5/6 NX TGR, as compared with RAS inhibition alone.
AIMS: There is evidence that in addition to hypertension and hyperactivity of the renin-angiotensin system (RAS), enhanced intrarenal activity of endothelin (ET) system contributes to the pathophysiology and progression of chronic kidney disease (CKD). This prompted us to examine if this progression would be alleviated by addition of type A ET receptor (ETA) blockade to the standard blockade of RAS. MAIN METHODS: Ren-2 transgenic rats (TGR) after 5/6 renal ablation (5/6 NX) served as a model of CKD. For RAS inhibition a combination of angiotensin-converting enzyme inhibitor (trandolapril, 6 mg/L drinking water) and angiotensin II type 1 receptor blocker (losartan, 100 mg/L drinking water) was used. Alternatively, ETA receptor blocker (atrasentan, 5 mg·kg(-1)·day(-1) in drinking water) was added to the combined RAS blockade. The follow-up period was 44 weeks after 5/6 NX, and the rats' survival rate, systolic blood pressure (SBP), proteinuria and indices of renal glomerular damage were evaluated. KEY FINDINGS: The survival rate was at first improved, by either therapeutic regime, however, the efficiency of RAS blockade alone considerably decreased 36 weeks after 5/6 NX: final survival rate of 65% was significantly lower than 91% achieved with combined RAS and ETA receptor blockade. SBP was not affected by the addition of ETA blockade while proteinuria and renal glomerular damage were further reduced. SIGNIFICANCE: Our data show that a combined RAS and ETA receptor blockade exhibits additional beneficial effects on survival rate and the progression of CKD in 5/6 NX TGR, as compared with RAS inhibition alone.
Authors: Věra Čertíková Chábová; Petr Kujal; Petra Škaroupková; Zdeňka Varňourková; Šárka Vacková; Zuzana Husková; Soňa Kikerlová; Janusz Sadowski; Elzbieta Kompanowska-Jezierska; Iwona Baranowska; Sung Hee Hwang; Bruce D Hammock; John D Imig; Vladimír Tesař; Ludek Červenka Journal: Kidney Blood Press Res Date: 2018-03-06 Impact factor: 2.687