Transforming growth factor-b-dependent and -independent pathways of induction of tubulointerstitial fibrosis in β6-/- mice
Transforming growth factor-b-dependent and -independent pathways of induction of tubulointerstitial fibrosis in β6-/- mice
复制标题
DOI：
10.1016/s0002-9440(10)63486-4
复制
发表时间：
2003-10-01
影响因子：
6
通讯作者：
Fogo, AB
中科院分区：
文献类型：
--
作者：
Ma, LJ;Yang, HC;Fogo, AB
转化生长因子-β 1（TGF-β 1）和肾素-血管紧张素-醛固酮系统是肾纤维化的关键介质。整合素α v β 6是一种在上皮细胞中表达的异源二聚体基质受体，结合并激活潜伏的TGF-β 1。我们使用β 6整联蛋白-Mill。小鼠（β 6（-/-）），以确定局部TGF-β 1活化在单侧输尿管梗阻（UUO）模型中肾纤维化中的作用。β 6（-/-）小鼠的梗阻肾脏显示出比野生型（WT）小鼠的梗阻肾脏更少的损伤，与较低的胶原蛋白I、胶原蛋白III、纤溶酶原激活物抑制剂（派-1）和TGF-β 1 mRNA水平以及较低的胶原蛋白含量相关。在β 6（-/-）UUO小鼠中输注血管紧张素H（Ang H）或醛固酮（Aldo）或其组合显著增加胶原蛋白含量，达到与相同治疗的WT相当的水平。与匹配的WT小鼠相比，在有或没有Ang H输注的UUO肾脏中，β 6（-/-）小鼠中活性TGF-β蛋白表达较少。β 6（-/-）阻塞肾脏中的活化Smad 2水平低于WT UUO小鼠，并且当通过Ang H输注在α 6（-/-）UUO小鼠中诱导纤维化时不增加。抗TGF-β抗体仅部分降低β 6（-/-）UUO肾脏中Ang U刺激的纤维化。原位杂交和免疫组织化学染色显示β 6（-/-）UUO肾组织中肾小管上皮细胞派-1 mRNA和蛋白表达较低，而Ang H、Aldo或两者联合作用时PAI-1表达增加。我们的研究结果表明，阻断α v β 6介导的TGF-β 1活化可以防止肾小管间质纤维化。此外，在阻塞的β 6（-/-）小鼠中，Ang H强烈诱导肾小管间质纤维化而不增加活化的Smad 2水平，表明存在通过血管紧张素诱导纤维化的TGF-β 1非依赖性途径。
Transforming growth factor-beta1 (TGF-beta1) and the renin-angiotensin-aldosterone system are key mediators in kidney fibrosis. Integrin alphavbeta6, a heterodimeric matrix receptor expressed in epithelia, binds and activates latent TGF-beta1. We used beta6 integrin-mill. mice (beta6(-/-)) to determine the role of local TGF-beta1 activation in renal fibrosis in the unilateral ureteral obstruction (UUO) model. Obstructed kidneys from beta6(-/-) mice showed less injury than obstructed kidneys from wild-type (WT) mice, associated with lower collagen I, collagen III, plasminogen activator inhibitor (PAI-1), and TGF-beta1 MRNA levels and lower collagen content. Infusion with either angiotensin H (Ang H) or aldosterone (Aldo) or combination in beta6(-/-) UUO mice significantly increased collagen contents to levels comparable to those in identically treated WT. Active TGF-beta protein expression in beta6(-/-) mice was less in UUO kidneys with or without Ang H infusion compared to matched WT mice. Activated Smad 2 levels in beta6(-/-) obstructed kidneys were lower than in WT UUO mice, and did not increase when fibrosis was induced in alpha6(-/-) UUO mice by Ang H infusion. Anti-TGF-beta antibody only partially decreased this Ang U-stimulated fibrosis in beta6(-/-) UUO kidneys. In situ hybridization and immunostaining showed low expression of PAI-1 mRNA and protein in tubular epithelium in beta6(-/-) UUO kidneys, with increased PAL I expression in response to Ang H, Aldo, or both. our results indicate that interruption of alphavbeta6-mediated activation of TGF-beta1 can protect against tubulointerstitial fibrosis. Further, the robust induction of tubulointerstitial fibrosis without increase in activated Smad 2 levels in obstructed,beta6(-/-) mice by Ang H suggests the existence of a TGF-beta1-independent pathway of induction of fibrosis through angiotensin.