Zhou Yong, Poczatek Maria H, Berecek Kathleen H, Murphy-Ullrich Joanne E
Department of Pathology and The Cell Adhesion and Matrix Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Biochem Biophys Res Commun. 2006 Jan 13;339(2):633-41. doi: 10.1016/j.bbrc.2005.11.060. Epub 2005 Nov 18.
Renal and cardiac fibrosis leading to organ failure are complications of both diabetes and hypertension. These disease processes, when combined, exacerbate development of fibrotic complications. Control of latent transforming growth factor (TGF)-beta activation is a potential determinant of fibrotic progression. Both glucose and angiotensin II (Ang II) upregulate thrombospondin-1 (TSP1), a major activator of latent TGF-beta, and stimulate increased TGF-beta activity. We previously showed that high glucose stimulated TSP1-dependent TGF-beta activation in rat mesangial cells (RMCs). In this paper, we examined whether Ang II similarly upregulates TSP1 production and TSP1-dependent TGF-beta activation alone or in combination with high glucose concentrations. Ang II and high glucose stimulated increases in TSP1 protein levels in the conditioned media of both rat cardiac fibroblasts (RCFs) and rat mesangial cells (RMCs). Meanwhile, Ang II stimulated increases in both TGF-beta activity and protein by RMCs, whereas, RCFs responded to both Ang II and high glucose with increased TGF-beta activity in the absence of altered TGF-beta protein levels. A combination of Ang II and high glucose induced synergistic TGF-beta activation by RCFs. Moreover, Ang II induction of TSP1 and increased TGF-beta activity were blocked by losartan, an antagonist of the Ang II type 1 (AT1) receptor. The increase in TSP1 expression leads to increased TGF-beta activity upon Ang II and/or glucose treatment, since peptide antagonists of TSP1-mediated TGF-beta activation blocked Ang II and glucose-induced TGF-beta activation. Our data support a role for TSP1 in the development and progression of renal and cardiac fibrosis in hypertension and diabetes.
导致器官衰竭的肾纤维化和心脏纤维化是糖尿病和高血压的并发症。这些疾病过程合并时，会加剧纤维化并发症的发展。控制潜伏转化生长因子（TGF）-β的激活是纤维化进展的一个潜在决定因素。葡萄糖和血管紧张素II（Ang II）均会上调血小板反应蛋白-1（TSP1），这是潜伏TGF-β的主要激活剂，并刺激TGF-β活性增加。我们之前表明，高糖刺激大鼠系膜细胞（RMCs）中TSP1依赖的TGF-β激活。在本文中，我们研究了Ang II是否同样单独或与高糖浓度联合上调TSP1的产生以及TSP1依赖的TGF-β激活。Ang II和高糖刺激大鼠心脏成纤维细胞（RCFs）和大鼠系膜细胞（RMCs）条件培养基中TSP1蛋白水平升高。同时，Ang II刺激RMCs中TGF-β活性和蛋白增加，而RCFs在TGF-β蛋白水平未改变的情况下，对Ang II和高糖均有TGF-β活性增加的反应。Ang II和高糖联合诱导RCFs产生协同性TGF-β激活。此外，Ang II诱导的TSP1和TGF-β活性增加被氯沙坦（一种Ang II 1型（AT1）受体拮抗剂）阻断。TSP1表达增加导致在Ang II和/或葡萄糖处理时TGF-β活性增加，因为TSP1介导的TGF-β激活的肽拮抗剂阻断了Ang II和葡萄糖诱导的TGF-β激活。我们的数据支持TSP1在高血压和糖尿病中肾纤维化和心脏纤维化的发生和发展中起作用。
