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Journal of Histochemistry and Cytochemistry, Vol. 47, 533-544, April 1999, Copyright © 1999, The Histochemical Society, Inc.

ARTICLE

Differential Expression of Thrombospondin and Cellular Fibronectin During Remodeling in Proliferative Glomerulonephritis

Jeffrey L. Barnesa,b, Ronda J. Mitchellb, John J. Kanalasc, and Veronique L. Barnesb
a The Medical Research Service, Audie Murphy Memorial Veterans Administration Hospital, San Antonio, Texas
b Department of Medicine, Division of Nephrology, The University of Texas Health Science Center, San Antonio, Texas
c Department of Medicine, Division of Nephrology, Thomas Jefferson University, Philadelphia, Pennsylvania

Correspondence to: Jeffrey L. Barnes, Dept. of Medicine, Div. of Nephrology, U. of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78284.

Thrombospondin-1 (TSP-1) and an alternatively spliced fibronectin (Fn)-EIIIA isoform are adhesive proteins associated with embryogenesis and tissue remodeling. We compared, by immunohistochemistry and in situ hybridization, the course of TSP-1 and Fn-EIIIA expression in a model of glomerulonephritis induced by Habu snake venom (HV) and characterized by mesangial cell migration, proliferation, and extracellular matrix (ECM) synthesis. At 24 hr after HV, TSP-1 and Fn-EIIIA proteins localized in the central aspects of lesions associated with platelets and macrophages and at the margins of lesions coinciding with mesangial cell migration (determined by Thy-1 staining). Mesangial cells at this time expressed TSP-1 but not Fn-EIIIA mRNA. TSP-1 protein and mRNA peaked in lesions at 48 hr and were associated with cell proliferation (determined by PCNA, {alpha}-smooth muscle actin phenotype, and expression of ß-PDGF receptor mRNA). TSP-1 expression declined at 72 hr when expression of ECM synthesis peaked, as determined by increased expression of collagen Type IV, laminin, and TGF-ß1 protein and mRNA. Mesangial cell expression of Fn-EIIIA was first observed at 48 hr and was most abundant at 72 hr after HV. Therefore, platelet- and macrophage-derived Fn-EIIIA and TSP-1 in early lesions are associated with mesangial cell migration. Mesangial cell upregulation of TSP-1 is associated with migration and proliferation but not maximal ECM accumulation, whereas mesangial cell expression of Fn-EIIIA is associated with proliferation and ECM accumulation. These results suggest distinctive temporal and spatial roles for TSP-1 and Fn-EIIIA in remodeling during glomerular disease. (J Histochem Cytochem 47:533–543, 1999)

Key Words: thrombospondin, alternatively spliced fibronectin, mesangial cell, migration, proliferation, extracellular matrix


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