Regulation of plasticity and fibrogenic activity of trabecular meshwork cells by Rho GTPase signaling.
Regulation of plasticity and fibrogenic activity of trabecular meshwork cells by Rho GTPase signaling.
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通过Rho GTPase信号传导调节小梁网细胞的可塑性和纤维化活性。
DOI：
10.1002/jcp.24524
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发表时间：
2014-07
影响因子：
5.6
通讯作者：
Rao, Ponugoti Vasantha
中科院分区：
文献类型：
--
作者：
Pattabiraman, Padmanabhan P.;Maddala, Rupalatha;Rao, Ponugoti Vasantha
青光眼是一种常见的致盲性疾病，通常与眼内压升高有关，这是由于通过小梁网（TM）的房水（AH）引流受损所致。尽管与细胞外基质（ECM）积累相关的TM组织收缩和刚度增加被认为是对AH流出的阻力增加的部分原因，但调节TM细胞收缩和ECM产生的细胞外线索和细胞内机制尚未明确。本研究测试了以下假设：由溶血磷脂酸（LPA）、TGF-β和结缔组织生长因子（CTGF）诱导的Rho GT3信号传导的持续激活影响TM细胞可塑性和纤维化活性，这可能最终影响对AH流出的抵抗。使用人TM细胞进行的各种实验显示，组成型活性RhoA（RhoAV 14）、TGF-β2、LPA和CTGF显著增加成纤维细胞特异性蛋白-1（FSP-1）、α-平滑肌肌动蛋白（αSMA）、胶原-1A1和分泌性总胶原的水平和表达，如通过q-RT-PCR、免疫荧光、免疫印迹、流式细胞术和Sircol测定所确定的。值得注意的是，这些变化似乎是由血清反应因子（SRF）、肌红蛋白相关转录因子（MRTF-A）、Slug和Twist-1介导的，它们是已知控制细胞可塑性、肌成纤维细胞生成/活化和纤维化活性的转录调节因子。此外，发现Rho激酶抑制剂Y27632和抗纤维化剂吡非尼酮均抑制TGF-β2诱导的αSMA、FSP-1和胶原-1A1的表达。总之，这些观察结果表明RhoA/Rho激酶信号传导在调节TM细胞可塑性、纤维化活性和肌成纤维细胞活化中的重要性，这些事件对青光眼患者眼内压升高的病理生物学具有潜在意义。
Glaucoma, a prevalent blinding disease is commonly associated with increased intraocular pressure due to impaired aqueous humor (AH) drainage through the trabecular meshwork (TM). Although increased TM tissue contraction and stiffness in association with accumulation of extracellular matrix (ECM) are believed to be partly responsible for increased resistance to AH outflow, the extracellular cues and intracellular mechanisms regulating TM cell contraction and ECM production are not well defined. This study tested the hypothesis that sustained activation of Rho GTPase signaling induced by lysophosphatidic acid (LPA), TGF-β and connective tissue growth factor (CTGF) influences TM cell plasticity and fibrogenic activity which may eventually impact resistance to AH outflow. Various experiments performed using human TM cells revealed that constitutively active RhoA (RhoAV14), TGF-β2, LPA and CTGF significantly increase the levels and expression of Fibroblast Specific Protein-1 (FSP-1), α-smooth muscle actin (αSMA), collagen-1A1 and secretory total collagen, as determined by q-RT-PCR, immunofluorescence, immunoblot, flow cytometry and the Sircol assay. Significantly, these changes appear to be mediated by Serum Response Factor (SRF), myocardin-related transcription factor (MRTF-A), Slug and Twist-1, which are transcriptional regulators known to control cell plasticity, myofibroblast generation/activation and fibrogenic activity. Additionally, the Rho kinase inhibitor-Y27632 and anti-fibrotic agent-pirfenidone were both found to suppress the TGF-β2-induced expression of αSMA, FSP-1 and collagen-1A1. Taken together, these observations demonstrate the significance of RhoA/Rho kinase signaling in regulation of TM cell plasticity, fibrogenic activity and myofibroblast activation, events with potential implications for the pathobiology of elevated intraocular pressure in glaucoma patients.
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