ROLE OF SPARC IN THE MODULATION OF GLOMERULAR INJURY

University Of Washington, Seattle WA

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Abstract

SPARC (Secreted Protein Acidic and Rich in Cysteine) is a matricellular protein made by glomerular and interstitial cells with several properties that may be important in the renal response to injury including anti- adhesive and anti-proliferative effects as well as effects on synthesis and secretion of type I collagen. In studies in the original Projects 1 and 2, we found that SPARC was up-regulated by glomerular mesangial and epithelial cells as well as interstitial fibroblasts in response to several forms of renal injury, correlated with resolution of cell proliferation and co-localized with deposition of type I collagen was increased. When SPARC was infused in vivo in a rat model of mesangioproliferative glomerulonephritis, there was a marked up-regulation of TGFbeta, collagen I and fibronectin deposition in the mesangium and renal interstitium. In this project, we will further analyze the relationship between SPARC, TGFbeta cell proliferation and matrix deposition in renal disease. In Specific Aim #1 of this project, we will utilize glomerular mesangial and epithelial cells from SPARC knockout and wild-type mice as well as recombinant human SPARC (rSPARC) and several mutated SPARC proteins to explore the levels (transcriptional translational, post-translational) at which SPARC modulates production of TGFbeta isoforms, receptors and collagen I/IV production. We will attempt to restore collagen I production and rate of cell cycle traverse in SPARC knockout cells by addition of TGFbeta and/or rSPARC and we will define the sequences within SPARC responsible for effects on renal cell proliferation and collagen I/TGFbeta production utilizing mutated rSPARC proteins or transfected cDNA's. In Specific Aim #2, we will move to the in vivo setting and utilize SPARC knockout and wild-type mice as well as SPARC knockout mice expressing mutated SPARC to analyze the effect of SPARC and its individual domains on glomerular and interstitial cell proliferation, TGFbeta and collagen I deposition and glomerular epithelial cell detachment from basement membrane in vivo. These studies will provide new insights into the role of an important new molecule in modulating the renal response to injury and determining whether individual insults lead to resolution and repair or progression to end stage renal disease.