Long-term angiotensin II receptor blockade limits hypertension, aortic dysfunction, and structural remodeling in a rat model of chronic kidney disease

Omar Z. Ameer, Mark Butlin, Elena Kaschina, Manuela Sommerfeld, Alberto P. Avolio, Jacqueline K. Phillips

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

Background/Aims: Chronic kidney disease (CKD) is associated with large artery remodeling, endothelial dysfunction and calcification, with angiotensin II (Ang II) a known driver of these pathologies. We investigated long-term Ang II type 1 receptor inhibition with valsartan on aortic function and structure in the Lewis polycystic kidney (LPK) rat model of CKD. Methods: Mixed sex LPK and Lewis control (total n = 28) treated (valsartan 60 mg/kg/day p.o. from 4 to 18 weeks) and vehicle groups were studied. Functional responses to noradrenaline (NA), potassium chloride and endothelium-dependent and independent relaxations were investigated in vitro using acetylcholine hydrochloride (ACh) and sodium nitroprusside (SNP), respectively. Effects of the nitric oxide synthase (NOS) substrate L-arginine, NOS inhibitor L-NAME and cyclooxygenase inhibitor indomethacin on ACh responses were examined. Results: In the LPK, valsartan reduced systolic blood pressure and urinary protein, ameliorated exaggerated sensitivity to NA, and normalized endothelium-dependent (ACh-Rmax; 91 ± 7 vs. 59 ± 6%, p = 0.0001) and independent dysfunction (SNP-Rmax; 99 ± 1 vs. 82 ± 7%, p = 0.040), as well as improving NO-dependent relaxation (Rmax; -51 ± 6 vs. -26 ± 9%, p = 0.008). Valsartan also reduced aortic wall hypertrophy, elastin disruption/fragmentation, calcification, media cystic degeneration, and levels of matrix metalloproteinase 9. Conclusions: This study highlights the role of Ang II in driving vascular manifestations of CKD and indicates that early treatment can significantly limit pathological changes.

Original languageEnglish
Pages (from-to)216-229
Number of pages14
JournalJournal of Vascular Research
Volume53
Issue number3-4
DOIs
Publication statusPublished - 1 Dec 2016

Keywords

  • valsartan
  • chronic kidney disease
  • aorta
  • vascular remodeling
  • endothelium
  • nitric oxide
  • calcification

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