Dr. Inoue’s research has been focused on identifying the molecular mechanism of atherosclerosis and insulin resistance. Her seminal work published in Circulation 1998 identified the role of vascular endothelial cell growth factor (VEGF) in the pathogenesis of atherosclerosis in humans. Later, she identified a molecular mechanism underlying the oxidized LDL-mediated injury to vascular endothelial cells (ATVB 2001). Her recent research efforts unraveled the molecular mechanism of insulin resistance, which is the pathological link between diabetes and atherosclerosis. She discovered a new role of exocyst complex in glucose transporter trafficking in adipocytes (Nature 2003 and MBC 2006). Her current research efforts are focused on the pathogenesis of atherosclerosis and diabetic nephropathy.
Diabetes mellitus is the major cause of chronic kidney disease. Glomerular proteinuria or microalbuminuria is considered as a hallmark of progressive diabetic nephropathy. Selective filtration of proteins from blood to urine is regulated in an integrated manner by vascular endothelial cells, glomerular basement membrane (GBM), and podocytes. It has been speculated that the interaction between podocytes and GBM plays a critical role in regulating glomerular filtration. The molecular link between GBM and podocytes, however, has been poorly understood. The framework of GBM is defined by the network of type IV collagen, of which mutations cause Alport syndrome. Matrix metalloproteinase (MMP) family genes have evolved to negotiate extracellular matrix (ECM) proteins, particularly collagens. Among MMPs, membrane-anchored MMPs play a major role in physiological remodeling of type I and type IV collagens. The central hypothesis of this study is that MMP14 may regulate podocyte function by negotiating ECM environments in physiological settings. Our long-term goal is to shed new light on the role of MMP-ECM interaction in regulating podocyte function in a research effort to prevent and treat diabetic nephropathy. In alignment with the long-term goal, the objective in this proposal is to define the role of MMP14, the major pericellular collagenase, in regulating podocyte function in vitro and in vivo.
1. Inoue, M., Chang, L., Hwang, J., Chiang, S. H., and Saltiel, A. R. “The exocyst complex is required for targeting of Glut4 to the plasma membrane by insulin.” Nature, 2003;422(6932), 629-33.
2. Inoue, M., Chiang, S.H., Chang, L., Chen, X. W., and Saltiel, A.R. “Compartmentalization of the exocyst complex in lipid rafts controls glut4 vesicle tethering.” Mol Biol Cell, 2006;17(5):2302-11.
3. Lodhi, I. J., Chiang, S. H., Chang, L., Vollenweider, D., Watson, R. T., Inoue, M., Pessin, J. E., and Saltiel, A. R. “Gapex-5, a Rab31 Guanine Nucleotide Exchange Factor that Regulates Glut4 Trafficking in Adipocytes.” Cell Metab, 2007 Jan;5(1):59-72.
4. Chun, T. H., Inoue, M., Morisaki, H., Yamanaka, I., Miyamoto, Y., Okamura, T., Sato-Kusubata, K., Weiss S. J. “A Genetic Link between Obesity and MMP14-Dependent Adipogenic Collagen Turnover.” Diabetes 2010 Jul 26