CD44 and hyaluronan expression in the development of experimental crescentic glomerulonephritis

Abstract

SUMMARYCD44 is a widely expressed cell surface glycoprotein which is involved in both cell-matrix and cellcell interactions which regulate a variety of processes, including leucocyte migration and activation. Therefore, we examined the expression of CD44, and its major ligand hyaluronan, during the induction and progression of experimental glomerulonephritis. Antibody staining of normal rat kidney showed constitutive CD44 expression by resident glomerular macrophages, parietal epithelial cells, medullary and occasional cortical tubules. There was a marked increase in CD44 expression over days 1, 7 and 21 of rat crescentic anti-glomerular basement membrane (GBM) glomerulonephritis. Infiltrating monocytes and lymphocytes were CD44 þ , with ultrastructural studies showing high levels of CD44 expressed on the surface of lymphocytes adherent to activated endothelium. Marked hyaluronan deposition was seen in areas of fibrosis on days 7 and 21, such as glomerular crescents and the periglomerular area. Hyaluronan deposition was accompanied by the presence of many CD44 þ cells. Double immunohistochemistry showed that both CD44 þ ED1 þ macrophages and CD44 þ myofibroblasts (identified by expression of a-smooth muscle actin) were present in areas of fibrosis. There was also a dramatic increase in cortical tubular CD44 expression, which was most evident in areas of tubular damage. Although tubular epithelial cells expressed CD44 upon both the basolateral and luminal surface, CD44 expression was most prominent within tight junctions, suggesting a role for CD44-CD44 interactions in cell-cell adhesion within the tubule. Analysis of CD44 isoforms by reverse transcriptase-polymerase chain reaction (RT-PCR) showed that the standard form of CD44 predominated in both normal and diseased kidney. However, a series of alternatively spliced CD44 isoforms was also detected, whose expression was markedly increased during disease. At least seven isoforms containing the v6 domain were identified, with the smallest form representing activated T cells. In conclusion, CD44 is constitutively expressed in normal kidney and is dramatically up-regulated in rat anti-GBM disease, suggesting possible roles for the CD44-hyaluronan interaction in leucocyte recruitment, renal fibrosis and tubular cell-matrix and cell-cell interactions during the induction and progression of crescentic glomerulonephritis.

Macrophage Migration Inhibitory Factor Mediates Proliferative GN via CD74

“…The upregulation of CD44 in resident glomerular cells and the de novo expression in PECs during glomerular diseases was previously documented by us and others. 19,29,30 We extend these data herein by quantitative analyses of CD44 mRNA expression in microdissected glomeruli showing a significant, up to eightfold, upregulation of CD44 in RPGN and IgAN (Supplemental Figure 1B).…”

Correlation between nicotine-induced inhibition of hematopoiesis and decreased CD44 expression on bone marrow stromal cells

“…Furthermore, the endothelial cell ligand for CD44 expressed on HSPC is not known. Because CD44-CD44 homotypic interactions could be involved in cell-cell adhesion, 64 it is conceivable that CD44 expressed on the endothelium may serve as a ligand for CD44 expressed on HSPC. Therefore, reduction of CD44 expression on endothelial cells would lead to a decreased adhesion of HSPC to the endothelium and, as a consequence, inhibition of HSPC homing.…”

SHAP Potentiates the CD44-mediated Leukocyte Adhesion to the Hyaluronan Substratum

“…The roles of CD44-HA interaction in lymphocyte extravasation (5,6) and stromal interaction (7,8) have become evident not only in cell adhesion systems in vitro with cell monolayer or tissue sections, but also in systems in vivo using specific antibodies or CD44-null mice. These studies implicated that the CD44-HA interaction may underlie the pathogenesis of a wide range of disorders such as the autoimmune diseases, including arthritis (9 -11), encephalomyelitis (12), crescentic glomerulonephritis (13), and uveoretinitis (14); allergic diseases, including asthma (7) and contact dermatitis (15); inflammatory bowel disease (8,16); graft rejection (17); atherosclerosis (18); hepatitis (19); and lung inflammation (20). Depending on the diseases, the consequences of the interaction may either be inflammatory, for example in the autoimmune diseases, where its role in the recruitment and activation of circulating leukocytes is predominant, or anti-inflammatory, e.g.…”