How caveolae regulate extracellular matrix production in kidney mesangial cells

小凹如何调节肾系膜细胞的细胞外基质产生

• 批准号: 418591-2012
• 负责人: Krepinsky, Joan
• 金额: $ 1.89万
• 依托单位: McMaster University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2012
• 资助国家: 加拿大
• 起止时间: 2012-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=505747
• 关键词: How; caveolae; regulate; extracellular; matrix

Caveolae, membrane microdomains with a distinct lipid and protein composition, have recently emerged as important signaling mediators. Caveolae require the protein caveolin (cav) for their formation. This is primarily the family member cav-1, and mice deficient in this gene lack caveolae in tissue including kidney. Our studies show that kidney mesangial cells (MC) from these mice, deficient in cav-1 and caveolae, show defects in the production of extracellular matrix proteins including fibronectin and collagen I, as well as the profibrotic cytokine connective tissue growth factor (CTGF). Furthermore, signaling by another potent profibrotic cytokine, transforming growth factor ß1 (TGFß1) is also impaired. The mechanism underlying our observations, however, is unknown and forms the basis for the research program in this application. We will investigate how these two key profibrotic factors are regulated by caveolae. Our data show that CTGF transcript and protein levels are significantly reduced in these cells, both at baseline and in response to profibrotic stimuli. The first major goal is thus to determine the mechanism whereby CTGF production is defective. The second major goal is to determine the reasons for the inability of TGFß to stimulate the synthesis of matrix proteins in MC which lack cav-1/caveolae. In aggregate, our research will elucidate the mechanism of matrix regulation by caveolae in kidney cells. This is of importance given the observation that caveolae control matrix production very differently in other tissues, with exacerbation of fibrosis in heart and lung in the absence of caveolae. Given the fundamental importance of CTGF and TGFß to a wide range of physiological and pathophysiological processes, the detailed delineation of the contribution of caveolae to their signaling will have broad applicability.

小窝，膜微结构域与不同的脂质和蛋白质组成，最近出现的重要信号介质。小窝需要小窝蛋白（cav）来形成。这主要是家族成员cav-1，缺乏该基因的小鼠在包括肾脏在内的组织中缺乏小窝。我们的研究表明，肾系膜细胞（MC）从这些小鼠，缺乏cav-1和小窝，显示缺陷的生产细胞外基质蛋白，包括纤连蛋白和胶原蛋白I，以及促纤维化细胞因子结缔组织生长因子（CTGF）。此外，另一种有效的促纤维化细胞因子转化生长因子β 1（TGF β 1）的信号传导也受损。然而，我们观察到的机制尚不清楚，这是本申请研究计划的基础。我们将研究这两个关键的促纤维化因子是如何通过小窝调节的。我们的数据表明，CTGF转录和蛋白水平显着降低，在这些细胞中，无论是在基线和在响应促纤维化刺激。因此，第一个主要目标是确定CTGF产生缺陷的机制。第二个主要目标是确定TGF β不能刺激缺乏cav-1/caveolae的MC中基质蛋白合成的原因。总之，我们的研究将阐明肾细胞中小窝对基质调节的机制。这是重要的，因为观察到小窝控制基质的产生在其他组织中非常不同，在没有小窝的情况下，心脏和肺中的纤维化加剧。鉴于CTGF和TGF β对广泛的生理和病理生理过程的根本重要性，小窝对其信号传导的贡献的详细描述将具有广泛的适用性。