Nonproteolytic activation of prorenin contributes to development of cardiac fibrosis in genetic hypertension

Atsuhiro Ichihara, Yuki Kaneshiro, Tomoko Takemitsu, Mariyo Sakoda, Fumiaki Suzuki, Tsutomu Nakagawa, Akira Nishiyama, Tadashi Inagami, Matsuhiko Hayashi

研究成果: Article査読

227 被引用数 (Scopus)

抄録

In contrast to proteolytic activation of inactive prorenin by cleavage of the N-terminal 43 residue peptide, we found that prorenin is activated without proteolysis by binding of the prorenin receptor to the pentameric "handle region" I11PLLKK15P. We hypothesized that such activation occurs in hypertensive rats and causes cardiac renin-angiotensin system (RAS) activation and end-organ damage. To test this hypothesis, we devised methods of specifically inhibiting nonproteolytic activation by decapeptide spanning the pentameric handle region peptide as a decoy. In stroke-prone spontaneously hypertensive rats (SHRsp) fed a high-salt diet, arterial pressure started to rise significantly with a marked increase in the cardiac prorenin receptor mRNA level at 8 weeks of age, and cardiac fibrosis had developed by 12 weeks of age. By immunohistochemistry using antibodies to the active site of the renin molecule, we demonstrated increased proteolytic or nonproteolytic activation of prorenin in the heart but not in plasma of SHRsp. Continuous subcutaneous administration of the handle region peptide completely inhibited the increased staining by antibodies to the active site of the renin molecule, indicating the increased nonproteolytic but not proteolytic activation of prorenin in the heart of SHRsp. Administration of the handle region peptide also inactivated tissue RAS without affecting circulating RAS or arterial pressure and significantly attenuated the development and progression of cardiac fibrosis. These results clearly demonstrate the significant role of nonproteolytically activated tissue prorenin in tissue RAS activation leading to cardiac fibrosis and significant inhibition of the cardiac damage produced by chronic infusion of the handle region peptide.

本文言語English
ページ(範囲)894-900
ページ数7
ジャーナルHypertension
47
5
DOI
出版ステータスPublished - 2006 5月

ASJC Scopus subject areas

  • 内科学

フィンガープリント

「Nonproteolytic activation of prorenin contributes to development of cardiac fibrosis in genetic hypertension」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

引用スタイル