Differential regulation of elevated renal angiotensin II in chronic renal ischemia

Hirobumi Tokuyama, Koichi Hayashi, Hiroto Matsuda, Eiji Kubota, Masanori Honda, Ken Okubo, Ichiro Takamatsu, Satoru Tatematsu, Yuri Ozawa, Shu Wakino, Takao Saruta

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44 Citations (Scopus)

Abstract

The present study was undertaken to clarify the role of intrarenal angiotensin (Ang) II and its generating pathways in clipped and nonclipped kidneys of 4-week unilateral renal artery stenosis in anesthetized dogs. After 4 weeks, renal plasma flow (RPF) decreased in clipped and nonclipped kidneys (baseline, 59±3; clipped, 16±1; nonclipped, 44±2 mL/min; P<0.01, n=22). Renal Ang I levels increased only in clipped, whereas intrarenal Ang II contents were elevated in both clipped (from 0.7±0.1 to 2.0±0.2 pg/mg tissue) and nonclipped kidneys (from 0.6±0.1 to 2.5±0.3 pg/mg tissue). Intrarenal ACE activity was increased in nonclipped kidneys but was unaltered in clipped kidneys. An angiotensin receptor antagonist (olmesartan medoxomil) given into the renal artery markedly restored RPF, and dilated both afferent and efferent arterioles (using intravital videomicroscopy). Furthermore, in clipped kidneys, the elevated Ang II was suppressed by a chymase inhibitor, chymostatin (from 2.1±0.6 to 0.8±0.1 pg/mg tissue; P<0.05), but not by cilazaprilat. In nonclipped kidneys, in contrast, cilazaprilat, but not chymostatin, potently inhibited the intrarenal Ang II generation (from 2.4±0.3 to 1.5±0.2 pg/mg tissue; P<0.05). Finally, [Pro11-D-Ala12]Ang I (an inactive precursor that yields Ang II by chymase but not by ACE; 1 to 50 nmol/kg) markedly elevated intrarenal Ang II in clipped, but not in nonclipped, kidneys. In conclusion, renal Ang II contents were elevated in both clipped and nonclipped kidneys, which contributed to the altered renal hemodynamics and microvascular tone. Furthermore, the mechanisms for intrarenal Ang II generation differ, and chymase activity is enhanced in clipped kidneys, whereas ACE-mediated Ang II generation is possibly responsible for elevated Ang II contents in nonclipped kidneys.

Original languageEnglish
Pages (from-to)34-40
Number of pages7
JournalHypertension
Volume40
Issue number1
DOIs
Publication statusPublished - 2002 Jul 22

Keywords

  • Angiotensin II
  • Angiotensin-converting enzyme
  • Chymase
  • Ischemia
  • Nephropathy

ASJC Scopus subject areas

  • Internal Medicine

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  • Cite this

    Tokuyama, H., Hayashi, K., Matsuda, H., Kubota, E., Honda, M., Okubo, K., Takamatsu, I., Tatematsu, S., Ozawa, Y., Wakino, S., & Saruta, T. (2002). Differential regulation of elevated renal angiotensin II in chronic renal ischemia. Hypertension, 40(1), 34-40. https://doi.org/10.1161/01.HYP.0000022060.13995.ED