Addition of Endothelin A-Receptor Blockade Spoils the Beneficial Effect of Combined Renin-Angiotensin and Soluble Epoxide Hydrolase Inhibition: Studies on the Course of Chronic Kidney Disease in 5/6 Nephrectomized Ren-2 Transgenic Hypertensive Rats

Research output: Contribution to journalArticle

Authors

  • Věra Čertíková Chábová
  • Petr Kujal
  • Zdeňka Vaňourková
  • Petra Škaroupková
  • Janusz Sadowski
  • Elzbieta Kompanowska-Jezierska
  • Vladimír Tesař
  • Bruce Hammock
  • John Imig
  • Hana Maxová
  • Luděk Červenka
  • Ivana Vaněčková

External Institution(s)

  • Charles University
  • Institute for Clinical and Experimental Medicine
  • Polish Academy of Sciences
  • University of California at Davis
  • Czech Academy of Sciences

Details

Original languageEnglish (US)
Pages (from-to)1493-1505
Number of pages13
JournalKidney and Blood Pressure Research
Volume44
Issue number6
StatusPublished - Dec 1 2019
Peer-reviewedYes

Abstract

Introduction: Previous studies in Ren-2 transgenic hypertensive rats (TGR) after 5/6 renal ablation (5/6 NX) have shown that besides pharmacological blockade of the renin-angiotensin system (RAS) also increasing kidney tissue epoxyeicosatrienoic acids (EET) levels by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for degradation of EETs, and endothelin type A (ETA) receptor blockade retards chronic kidney disease (CKD) progression. This prompted us to evaluate if this progression will be alleviated by the addition of sEH inhibitor and ETA receptor antagonist to the standard complex blockade of RAS (angiotensin-converting enzyme inhibitor plus angiotensin II type 1 receptor blocker) in rats with established CKD. Methods: The treatment regimens were initiated 6 weeks after 5/6 NX in TGR, and the follow-up period was 60 weeks. Results: The addition of sEH inhibition to RAS blockade improved survival rate, further reduced albuminuria and renal glomerular and kidney tubulointerstitial injury, and attenuated the decline in creatinine clearance - all this as compared with 5/6 NX TGR treated with RAS blockade alone. Addition of ETA receptor antagonist to the combined RAS and sEH blockade not only offered no additional renoprotection but, surprisingly, also abolished the beneficial effects of adding sEH inhibitor to the RAS blockade. Conclusion: These data indicate that pharmacological strategies that combine the blockade of RAS and sEH could be a novel tool to combat the progression of CKD. Any attempts to further extend this therapeutic regimen should be made with extreme caution.

    Research areas

  • 5/6 Renal mass reduction, Chronic kidney disease, Endothelin A receptor blocker, Hypertension, Renin-angiotensin system, Soluble epoxide hydrolase inhibitor

Citation formats

APA

Čertíková Chábová, V., Kujal, P., Vaňourková, Z., Škaroupková, P., Sadowski, J., Kompanowska-Jezierska, E., ... Vaněčková, I. (2019). Addition of Endothelin A-Receptor Blockade Spoils the Beneficial Effect of Combined Renin-Angiotensin and Soluble Epoxide Hydrolase Inhibition: Studies on the Course of Chronic Kidney Disease in 5/6 Nephrectomized Ren-2 Transgenic Hypertensive Rats. Kidney and Blood Pressure Research, 44(6), 1493-1505. https://doi.org/10.1159/000504137

Harvard

Čertíková Chábová, V, Kujal, P, Vaňourková, Z, Škaroupková, P, Sadowski, J, Kompanowska-Jezierska, E, Tesař, V, Hammock, B, Imig, J, Maxová, H, Červenka, L & Vaněčková, I 2019, 'Addition of Endothelin A-Receptor Blockade Spoils the Beneficial Effect of Combined Renin-Angiotensin and Soluble Epoxide Hydrolase Inhibition: Studies on the Course of Chronic Kidney Disease in 5/6 Nephrectomized Ren-2 Transgenic Hypertensive Rats', Kidney and Blood Pressure Research, vol. 44, no. 6, pp. 1493-1505. https://doi.org/10.1159/000504137