The purpose of these studies is to determine the molecular mechanisms responsible for the regulation of extracellular matrix proteins, to explore inducible factors that modulate mitogenesis and cellular matrix protein production such as hormones, autacoids, cytokines, and growth factors, and to develop novel therapeutic strategies to prevent progressive fibrosis and sclerosis. To accomplish these goals, we have focused on the normal regulation of the extracellular matrix during nephrogenesis and the mechanisms responsible for abnormal metabolism of extracellular matrix in renal disease states. During renal development, basement membrane genes are expressed in a coordinated fashion in different portions of the nephron. After nephrogenesis is complete and during adult life, matrix proteins are synthesized at low levels, presumably representing on-going replacement and remodeling of basement membrane and mesangial matrix. A common feature of the renal response to metabolic injury or inflammation is increased deposition of extracellular matrix proteins. The kidney is exquisitely sensitive to this process since normal renal function is predicated on a precise structure-function relationship. Thus, scarring anywhere along the nephron threatens the overall filtration process. Recent studies have 1. uncovered a novel role for products of arachidonic acid metabolism in the regulation of the renal mesangial matrix, 2. defined a new interrelationship for TGF-beta2 and the renin-angiotensin system, 3. defined the cis-acting elements within the promoter of the TGF-beta2 gene, and 4.demonstrated an important role for TGF-beta in the regulation of metalloproteinases.
