title: Addition of ET(A) receptor blockade increases renoprotection provided by renin-angiotensin system blockade in 5/6 nephrectomized Ren-2 transgenic rats.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Nephrology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Věra
authors.initials: V
authors.lastname: Čertíková Chábová
authors.affiliation: Department of Pathology, 3rd Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Vernerová
authors.affiliation: Department of Pathology, 3rd Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Kujal
authors.affiliation: Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Husková
authors.affiliation: Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Škaroupková
authors.affiliation: Department of Nephrology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Vladimír
authors.initials: V
authors.lastname: Tesař
authors.affiliation: Section of Nephrology, Medical Policlinic, Department of Medicine, University of Bonn, Bonn, Germany.
authors.forename: Herbert J
authors.initials: HJ
authors.lastname: Kramer
authors.affiliation: Department of Renal and Body Fluid Physiology, M. Mossakowski Medical Research Centre, Polish Academy of Science, Warsaw, Poland.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Kompanowska-Jezierska
authors.affiliation: Department of Renal and Body Fluid Physiology, M. Mossakowski Medical Research Centre, Polish Academy of Science, Warsaw, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Walkowska
authors.affiliation: Department of Renal and Body Fluid Physiology, M. Mossakowski Medical Research Centre, Polish Academy of Science, Warsaw, Poland.
authors.forename: Janusz
authors.initials: J
authors.lastname: Sadowski
authors.affiliation: Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Luděk
authors.initials: L
authors.lastname: Červenka
authors.affiliation: Institute of Physiology v.v.i., Academy of Sciences of the Czech Republic, Prague, Czech Republic. Electronic address: ivanava@biomed.cas.cz.
authors.forename: Ivana
authors.initials: I
authors.lastname: Vaněčková
mesh_terms: D000804:Angiotensin II / Q000097:blood; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D065128:Endothelin Receptor Antagonists / Q000627:therapeutic use*; D019332:Endothelin-1 / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007674:Kidney Diseases / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D009392:Nephrectomy; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D044022:Receptor, Endothelin A / Q000378:metabolism*; D012083:Renin / Q000235:genetics*; D012084:Renin-Angiotensin System / Q000187:drug effects*; D013599:Systole / Q000187:drug effects
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D020011:Protective Agents; D044022:Receptor, Endothelin A; C535029:Ren2 protein, rat; D000804:Angiotensin II; D012083:Renin
keywords: 5/6 nephrectomy; Chronic kidney disease; End-organ damage; Endothelin receptor type A; Hypertension