How caveolae regulate extracellular matrix production in kidney mesangial cells

小泡是一种具有不同脂质和蛋白质组成的膜微结构域，近年来作为重要的信号介质出现。小窝的形成需要蛋白质小窝蛋白（cav）。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泡。我们的研究表明，来自这些小鼠的肾系膜细胞（MC）缺乏cav-1和小泡，在细胞外基质蛋白（包括纤维连接蛋白和胶原I）以及促纤维化细胞因子结缔组织生长因子（CTGF）的产生方面存在缺陷。此外，另一种强效促纤维化细胞因子转化生长因子ß1 （TGFß1）的信号传导也受损。然而，我们的观察结果背后的机制是未知的，并构成了本应用程序研究计划的基础。我们将研究这两个关键的促纤维化因子是如何被小泡调节的。我们的数据显示，CTGF转录物和蛋白水平在这些细胞中显著降低，无论是在基线水平还是在对促纤维化刺激的反应中。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TGFß无法刺激缺乏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泡调节基质的机制。这一点很重要，因为观察到在其他组织中，小泡对基质生成的控制非常不同，在没有小泡的情况下，心脏和肺的纤维化会加剧。鉴于CTGF和TGFß在广泛的生理和病理生理过程中具有重要的基础性作用，因此详细描述小泡对其信号传导的贡献将具有广泛的适用性。

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.