Glomerular mesangial cells seem to regulate glomerular hemodynamics by their contractile function. Alterations to the contractile properties of these cells in diabetes mellitus could result in glomerulosclerosis by a hemodynamic mechanism. Cultured mesangial cells undergo a calcium-dependent contraction when treated with angiotensin II and vasopressin. Associated with contraction induced by vasopressin, there is an accelerated turnover of phosphotidylinositol. This is often referred to as the """"""""PL effect"""""""" and it has been reported to play an important role in hormone-mediated intracellular events that require calcium. Inositol, which is a growth factor for many cell types as well as a necessary substrate for phosphatidylinositol synthesis, is deficient in diabetes mellitus. Thus, under these circumstances mesangial cell growth and function may be seriously compromised. In this application, we propose to study inositide metabolism and function in cultured mesangial cells under baseline and hormone-stimulated conditions (with angiotensin II and arginine vasopressin). These same metabolic studies will be conducted in cultured mesangial cells under conditions of inositol deficiency, and imposed glucose excess. In addition, studies will be initiated to determine if correction of the inositol defect by dietary supplementation or Sorbinil treatment in experimental models of diabetes mellitus will ameliorate the glomerulosclerosis.
