How caveolae regulate extracellular matrix production in kidney mesangial cells

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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.