ECM Remodeling in Diabetic Kidney Disease
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.