Podocyte Expression of Osteopontin and FSP-1/S100A4 in Human Crescentic Glomerulonephritis

Abstract

Crescents have been described as a mixture of monocytes/ macrophages, glomerular parietal epithelial cells, and myofibroblasts; however, the cellular components of crescents still remain controversial. Podocytes have not been thought to be involved in crescents; this is because markers for the podocyte phenotype have been rarely reported in crescents. However, studies have shown that podocytes form bridges between the glomerular capillary tufts and Bowman’s capsule during the early phase of disease in an anti-glomerular basement membrane (GBM) nephritis mouse model. Both in Wilms tumor suppressor protein 1 (WT1) and synaptopodin, podocyte phenotype markers have been reported to be negative. However, the galactosidase gene-transfected podocytes have been shown to populate cellular crescents in an anti-GBM nephritis mouse model. In addition, nestin-positive podocytes contribute to crescent formation in human crescentic glomerulonephritis (CrGN). Such observations suggest that podocytes play a central role in early cellular crescent formation by migrating and adhering to Bowman’s capsule. Osteopontin (OPN) is a secreted or a matrix type, Cadependent and highly acidic phosphorylated glycoprotein. The secreted OPN is cleaved by thrombin into two soluble segments, but one, interacting with integrin ανβ3, is six amino acids to the COOH-terminal side of Arg-Gly-Asp (RGD) sequences. OPN mediates cell-matrix adhesion and delays survival by intracellular signaling that changes the focal adhesion kinase status by interacting with ανβ3 integrin, in a RGD sequence dependent manner. The other one, produced by thrombin cleavage, that is congruous with the COOH-terminal motif of OPN, is also detected in certain physiological and pathological conditions. The autocrine incursion of CD44ν6 by soluble OPN, can induce the loosening of cell-matrix adhesion and contributes to cell migration via Rho family GTPase activation. As matrix components, OPN and hyaluronate (HA) competitively interact with CD44; HA, but not OPN, induces standard CD44 (CD44s)-dependent cell-matrix adhesion and cell-cell aggregation. In human CrGN, integrin ανβ3 expression has been reported to increase in the podocytes of glomerular capillary tufts and in distal tubular epithelial cells; otherwise, CD44s expression has been shown in cellular components of the crescents, as well as in a rat model. In murine models of CrGN, OPN expresPodocyte Expression of Osteopontin and FSP-1/S100A4 in Human Crescentic Glomerulonephritis