Mesangial cell-predominant functional gene, megsin.

We obtained the "gene profile" of cultured human mesangial cells, and discovered five unknown genes predominantly expressed in mesangial cells. Megsin is one of these novel genes, and sequencing analysis of megsin showed that megsin belongs to the serpin (serine protease inhibitor) superfamily. The characteristics of megsin as a functional serpin are highly conserved among different species, including mice and rats. Expression of megsin is up-regulated in a variety of diseases with mesangial injury in humans and in animal models. We analyzed the promoter region of megsin and identified one positive regulatory motif, an incomplete activator protein-1 (AP-1) binding site within the region. Transgenic mice overexpressing megsin developed mesangial expansion and hypercellularity, which was associated with glomerular immune complex deposition. Our in vitro assays identified plasmin as a candidate target of megsin, although it is likely that megsin has other biological ligands in vivo. These results suggest that megsin plays an essential role in modulating the biological functions of mesangial cells. Megsin may play a role in the regulation of a wide variety of processes in mesangial cells, such as matrix metabolism, cell proliferation, and apoptosis. Identification of the exact biological functions and target proteases of megsin will lead us to develop novel therapeutic approaches to glomerular diseases.