title: Angiotensin-(1-7) activates growth-stimulatory pathways in human mesangial cells.
abstract: 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 AT(1) receptor antagonist losartan, nor the AT(2) antagonist PD123319 affected specific binding of [(125)I]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-beta1 (TGF-beta1), fibronectin, and collagen IV. Both A-779 and SB202190 blocked the Ang-(1-7)-stimulated increases in TGF-beta1, 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-beta1 and extracellular matrix proteins. We conclude that Ang-(1-7) exerts growth-stimulatory effects in human mesangial cells.
authors.affiliation: Div. of Nephrology, Dept. of Medicine, Kidney Research Centre, Ottawa Health Research Institute, Univ. of Ottawa, 1967 Riverside Dr., Rm. 535, Ottawa, Ontario, Canada K1H7W9.
authors.forename: Joseph
authors.initials: J
authors.lastname: Zimpelmann
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Burns
mesh_terms: D000803:Angiotensin I / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D024141:Collagen Type IV / Q000096:biosynthesis; D000242:Cyclic AMP / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D005353:Fibronectins / Q000096:biosynthesis; D006801:Humans; D020935:MAP Kinase Signaling System; D050527:Mesangial Cells / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D054467:Phospholipases A2 / Q000378:metabolism; D010766:Phosphorylation; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis
chemical_list: D024141:Collagen Type IV; D005353:Fibronectins; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D053773:Transforming Growth Factor beta1; D016718:Arachidonic Acid; D004247:DNA; D000803:Angiotensin I; D000242:Cyclic AMP; D020928:Mitogen-Activated Protein Kinases; D054467:Phospholipases A2; C118790:angiotensin I (1-7); D002118:Calcium