HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) A corrigendum has been published All Versions of this Article: 296/2/F337    most recent 90437.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Zimpelmann, J. Articles by Burns, K. D. Search for Related Content PubMed PubMed Citation Articles by Zimpelmann, J. Articles by Burns, K. D.

Angiotensin-(1–7) activates growth-stimulatory pathways in human mesangial cells

Division of Nephrology, Department of Medicine, Kidney Research Centre, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada

Submitted 25 July 2008 ; accepted in final form 28 November 2008

Angiotensin-(1–7) [Ang-(1–7)] is generated in part via ACE2-dependent degradation of angiotensin II (ANG II). In proximal tubular cells, Ang-(1–7) inhibits ANG II-stimulated phosphorylation of the mitogen-activated protein kinases (MAPKs) p38, extracellular signal-related kinase (ERK1/ERK2), and c-jun N-terminal kinase (JNK), suggesting that Ang-(1–7) protects against ANG II-mediated tubulointerstitial injury. We determined the effect of Ang-(1–7) on signaling and growth responses in cultured human mesangial cells. Ang-(1–7) increased phosphorylation of p38, ERK1/ERK2, and JNK MAPKs, which was blocked by the Ang-(1–7) antagonist A-779. Neither the AT₁ receptor antagonist losartan, nor the AT₂ antagonist PD123319 affected specific binding of [¹²⁵I]Ang-(1–7) or Ang-(1–7)-stimulated p38 phosphorylation. Ang-(1–7) increased cell arachidonic acid release, an effect blocked by A-779. The p38 MAPK antagonist SB202190 completely prevented Ang-(1–7)-stimulated release of arachidonic acid, whereas inhibitors of ERK or JNK had no effect. Ang-(1–7) significantly enhanced DNA synthesis and increased production of transforming growth factor-β1 (TGF-β1), fibronectin, and collagen IV. Both A-779 and SB202190 blocked the Ang-(1–7)-stimulated increases in TGF-β1, fibronectin, and collagen IV. These data indicate that Ang-(1–7) activates MAPK phosphorylation via binding to a specific receptor in human mesangial cells. Stimulation of p38 MAPK phosphorylation by Ang-(1–7) leads to release of arachidonic acid and production of TGF-β1 and extracellular matrix proteins. We conclude that Ang-(1–7) exerts growth-stimulatory effects in human mesangial cells.

renin-angiotensin system; glomerulus; receptor Mas; extracellular matrix protein; transforming growth factor-β1