Tyrosine phosphorylation of the LDL receptor‐related protein (LRP) and activation of the ERK pathway are required for connective tissue growth factor to potentiate myofibroblast differentiation
Tyrosine phosphorylation of the LDL receptor‐related protein (LRP) and activation of the ERK pathway are required for connective tissue growth factor to potentiate myofibroblast differentiation
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结缔组织生长因子增强肌成纤维细胞分化需要 LDL 受体相关蛋白 (LRP) 的酪氨酸磷酸化和 ERK 通路的激活
DOI：
10.1096/fj.04-2357fje
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Haiyan Wang
中科院分区：
文献类型：
--
作者：
Min Yang;Hai;Jing;Dongxia Li;Haiyan Wang
肾肌成纤维细胞在肾纤维化过程中过量细胞外基质的积累中起关键作用。转化生长因子- β1 （tgf - β1）和结缔组织生长因子（CTGF）都是重要的促纤维化生长因子，它们在纤维化的发病过程中相互作用。在这项研究中，我们证明CTGF单独对肾间质成纤维细胞的肌成纤维细胞转化和纤维连接蛋白分泌没有影响，而CTGF与TGFβ1联合培养增强了TGFβ1的反应，包括肌成纤维细胞活化、α‐SMA的新生表达和纤维连接蛋白的细胞外积累。CTGF诱导成纤维细胞中低密度脂蛋白受体相关蛋白（LRP）胞质域的tryrosine磷酸化，LRP拮抗剂受体相关蛋白（RAP）抑制CTGF诱导的LRP的tryrosine磷酸化。LRP信号的抑制降低了CTGF介导的α - SMA蛋白的协同诱导。此外，CTGF的增强作用既不依赖于TGFβ1诱导的Smad2磷酸化及其与Smad4的关联，也不是由活化的Smad2的核积累引起的。当TGFβ1‐预处理的成纤维细胞与CTGF孵育时，观察到ERK1/2 MAPK信号的激活。MEK1抑制剂PD98059对ERK活化的抑制与CTGF促进的α - SMA蛋白表达的降低有关。我们的体外研究提供了证据，证明CTGF增强TGFβ1介导的肌成纤维细胞分化并激活分化的肌成纤维细胞。
Renal myofibroblasts play a crucial role in the accumulation of excess extracellular matrix during renal fibrosis. Both transforming growth factor‐β1 (TGFβ1) and connective tissue growth factor (CTGF) are important profibrotic growth factors, which interact in the pathogenesis of fibrosis. In this study, we demonstrate that CTGF alone has no influence on myofibroblast transformation and fibronectin secretion in kidney interstitial fibroblasts, whereas incubation of CTGF in combination with TGFβ1 enhanced TGFβ1 responses, including myofibroblast activation, de novo expression of α‐SMA, and extracellular accumulation of fibronectin. CTGF induced tryrosine phosphorylation of the cytoplasmic domain of the low‐density lipoprotein receptor‐associated protein (LRP) in fibroblasts, and the LRP‐antagonist, receptor‐associated protein (RAP) inhibited CTGF‐induced tryrosine phosphorylation of LRP. Inhibition of LRP signaling reduced CTGF‐mediated synergistic induction of α‐SMA protein. Furthermore, the potentiating action of CTGF was neither dependent on modulation of TGFβ1‐induced Smad2 phosphorylation and its association with Smad4, nor did it result from nuclear accumulation of activated Smad2. When TGFβ1‐pretreated fibroblasts were incubated with CTGF, activation of ERK1/2 MAPK signaling was observed. Inhibition of ERK activation by the MEK1 inhibitor PD98059 was associated with a reduction of CTGF‐promoted α‐SMA protein expression. Our in vitro studies provide evidence that CTGF potentiates TGFβ1‐mediated myofibroblast differentiation and activates differentiated myofibroblasts.
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影响因子：
6.5
作者：
Frazier, K;Williams, S;Grotendorst, GR
通讯作者：
Grotendorst, GR
DOI：
10.1097/01.asn.0000099373.33259.b2
发表时间：
2003-12-01
影响因子：
13.6
作者：
Yang, JW;Mang, XH;Liu, YH
通讯作者：
Liu, YH
DOI：
--
发表时间：
1994-07
期刊：
The American journal of pathology
影响因子：
--
作者：
Kai Zhang;M. Rekhter;D. Gordon;S. Phan
通讯作者：
Kai Zhang;M. Rekhter;D. Gordon;S. Phan
影响因子：
6
作者：
Yang, JW;Dai, CS;Liu, YH
通讯作者：
Liu, YH
角膜肌成纤维细胞分化过程中转化生长因子-β刺激结缔组织生长因子的表达。
DOI：
--
发表时间：
2001
期刊：
Investigative ophthalmology & visual science.
影响因子：
--
作者：
Folger,PA;Zekaria,D;Grotendorst,G;Masur,SK
通讯作者：
Masur,SK