Secreted protein acidic and rich in cysteine deficiency ameliorates renal inflammation and fibrosis in angiotensin hypertension
Secreted protein acidic and rich in cysteine deficiency ameliorates renal inflammation and fibrosis in angiotensin hypertension
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DOI：
10.2353/ajpath.2007.061273
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发表时间：
2007-10-01
影响因子：
6
通讯作者：
Motamed, Kouros
中科院分区：
文献类型：
--
作者：
Socha, Matthew J.;Manhiani, Marlina;Motamed, Kouros
基质细胞门蛋白分泌富含半胱氨酸的酸性蛋白 (SPARC) 调节细胞粘附、增殖、基质沉积和组织重塑。 SPARC 已被证明可以调节系膜细胞中 I 型胶原蛋白和转化生长因子-β 1 的表达，并且在大鼠血管紧张素 (ANG) II 输注模型中的肾小管间质纤维化过程中高度表达。我们假设 SPARC 是 ANG II 的下游效应子，宿主 SPARC 功能的丧失对与 ANG U 高血压相关的肾损伤和纤维化具有保护作用。我们的结果表明，培养的原代系膜细胞响应 ANG II，表现出浓度依赖性的 SPARC 表达增加。与野生型高血压对照相比，慢性输注 ANG U 14 天后，高血压 SPARC 缺失小鼠表现出尿路和肾脏氧化应激和炎症指标水平显着降低，肾血管周围和肾小管间质纤维化减少。此外，发现 SPARC 无效小鼠中观察到的肾脏保护变化与血压无关。这些结果表明 SPARC 是 ANG H 信号传导的效应器，并表明 SPARC 在介导 ANG H 诱导的氧化应激、炎症和纤维化中发挥着重要作用。
The matricelhilar protein secreted protein acidic and rich in cysteine (SPARC) modulates cell adhesion, proliferation, matrix deposition, and tissue remodeling. SPARC has been shown to regulate the expression of collagen type I and transforming growth factor-beta 1 in mesangial cells and to be highly expressed during tubulointerstitial fibrosis in rat angiotensin (ANG) II infusion models. We hypothesized that SPARC is a downstream effector of ANG II and that loss of host SPARC function provides a protective effect on renal damage and fibrosis associated with ANG U hypertension. Our results revealed that cultured primary mesangial cells displayed a concentration-dependent increase in SPARC expression in response to ANG II. After a 14-day chronic infusion of ANG U, hypertensive SPARC-null mice exhibited significantly attenuated levels of urinary and renal indicators of oxidative stress and inflammation and decreased renal perivascular and tubulointerstitial fibrosis relative to wildtype hypertensive controls. Moreover, the observed renal protective changes in SPARC-null mice were found to be independent of blood pressure. These results identify SPARC as an effector of ANG H signaling and suggest an important role for SPARC in mediating ANG H-induced oxidative stress, inflammation, and fibrosis.