Zimpelmann Joseph, Burns Kevin D
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.
Am J Physiol Renal Physiol. 2009 Feb;296(2):F337-46. doi: 10.1152/ajprenal.90437.2008. Epub 2008 Dec 3.
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.
血管紧张素 -（1 - 7）[Ang -（1 - 7）]部分是通过血管紧张素转换酶2（ACE2）依赖的血管紧张素II（ANG II）降解产生的。在近端肾小管细胞中，Ang -（1 - 7）抑制ANG II刺激的丝裂原活化蛋白激酶（MAPKs）p38、细胞外信号调节激酶（ERK1/ERK2）和c - jun氨基末端激酶（JNK）的磷酸化，这表明Ang -（1 - 7）可防止ANG II介导的肾小管间质损伤。我们确定了Ang -（1 - 7）对培养的人系膜细胞信号传导和生长反应的影响。Ang -（1 - 7）增加了p38、ERK1/ERK2和JNK MAPKs的磷酸化，这被Ang -（1 - 7）拮抗剂A - 77所阻断。血管紧张素II 1型（AT1）受体拮抗剂氯沙坦和血管紧张素II 2型（AT2）受体拮抗剂PD123319均不影响[125I]Ang -（1 - 7）的特异性结合或Ang -（1 - 7）刺激的p38磷酸化。Ang -（1 - 7）增加了细胞花生四烯酸的释放，这一作用被A - 779阻断。p38 MAPK拮抗剂SB202190完全阻止了Ang -（1 - 7）刺激的花生四烯酸释放，而ERK或JNK抑制剂则无此作用。Ang -（1 - 7）显著增强了DNA合成，并增加了转化生长因子 -β1（TGF -β1）、纤连蛋白和IV型胶原的产生。A - 779和SB202190均阻断了Ang -（1 - 7）刺激的TGF -β1、纤连蛋白和IV型胶原的增加。这些数据表明，Ang -（1 - 7）通过与人系膜细胞中的特定受体结合来激活MAPK磷酸化。Ang -（1 - 7）刺激p38 MAPK磷酸化导致花生四烯酸释放以及TGF -β1和细胞外基质蛋白的产生。我们得出结论，Ang -（1 - 7）在人系膜细胞中发挥生长刺激作用。
