MOTILITY FACTORS IN RENAL FIBROGENESIS

Barnes-Jewish Hospital, Saint Louis MO

Investigators

Linked publications & trials

Abstract

DESCRIPTION (Abstract of the project) 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 its 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, osteopontin expression in renal tubular cells is stimulated. We have developed a model of renal fibrogenesis following UUO during which OPN is rapidly upregulated. We propose to analyze the function of OPN is renal fibrogenesis utilizing unique resources provided by several knockout mouse models. Studies will examine osteopontin as a chemotactic cytokine important in the macrophage infiltration of the renal tubular interstitium following ureteral obstruction. Further studies will analyze the role of osteopontin as 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 avB3 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 avB3 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 macro-molecular structures stabilizing the pathologic fibrotic matrix of the diseased kidney. These studies will carefully analyze 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.