Osteopontin (OPN) is a multi-functional protein originally discovered as a non-collagenous bone matrix protein. Considerable recent data and information deduced from mice genetically engineered null for OPN suggests that is major function may be other than a cell/matrix-matrix/cell adhesion protein. Osteopontin is produced in numerous tissues in response to injury. In numerous renal disease states, expression in renal tubular cells is stimulated. We have developed a model of renal fibrogenesis following unilateral ureteral obstruction during which OPN is rapidly up-regulated. We propose to analyze the function of OPN is renal fibrogenesis utilizing unique resources provided by several knockout mouse models. Studies will examine osteopontin is a chemotactic cytokine important in the macrophage infiltration of the renal tubular interstitium following ureteral obstruction. Further studies will analyze the role of osteopontin is a cytoprotective factor effecting the rates of renal tubular apoptosis following ureteral obstruction. Signal transduction studies will be performed utilizing a mouse model engineered null for one of the osteopontin receptors, the alphavbeta3 integrin. Additional studies will examine the function of osteopontin as a matrix protein. We will examine incorporation of osteopontin into the extracellular matrix under the influence of alphavbeta3 and tissue transglutaminase which we have also shown to be up-regulated following ureteral obstruction. Our hypothesis is that OPN is incorporated by cross- linking into macromolecular structures stabilizing the pathologic fibrotic matrix of the diseased kidney. These studies will carefully analyzed the functional role of osteopontin in this model of renal fibrogenesis and lead to the development of additional experimental strategies that may serve to ameliorate fibrogenesis and be applicable to several renal disease.
