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

Joseph Zimpelmann, Kevin D. Burns

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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


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