Patients with focal segmental glomerular sclerosis and other glomerular sclerotic processes often progress to renal failure, with proteinuria and recognized abnormalities of glomerular hemodynamics. This sclerosis is composed of normal collagenous components of the matrix, the glomerular basement membranes. We envision sclerosis as a loss of control over production of matrix by intrinsic glomerular cells. In the mesangium, expanded myosin can represent smooth muscle mesangial cell hypertrophy. This can be turned on by increased intra-glomerular blood pressure or flow, by circulating mediators or infiltrating inflammatory cells, or by the epithelial cell responding locally, losing its capacity to inhibit the mesangial cell. For the epithelial cell, the stimulus for causing excessive matrix (by itself or by the mesangial cell) can be a sensitivity to proteins that are normally not filtered and therefore not seen by the epithelial cell. To separate these elements, we have characterized two human glomerular cell types in culture, the smooth-muscle like mesangial cells and the contact-inhibited epithelial cells. We have shown their synthesis of basement-membrane collagens. We will now first establish differentiation by immunochemical techniques for cells maintained in a non-proliferative state. We will then quantitate their collagen synthesis by the techniques of molecular biology (mRNA) and biochemistry. To determine the effects of factors potentially inciting the development of glomerular sclerosis, by uncontrolled synthesis of basement membrane components, we will examine the effects of mediators of muscle cell contraction and inflammation on mesangial cells, and that of normal plasma proteins and inflammatory stimuli, including immune injury, on epithelial cell differentiation and GBM synthesis. Finally, the effects of the two cells will be combined, to explore the requirement for a cooperative signal in the development of sclerosis. It is expected that learning the mechanism of control over glomerular cells in culture will help to prevent the obliteration of normal glomerular architecture by glomerular sclerosis and the resulting catastrophic loss of renal function in many renal diseases.
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