CD44 AND HYALURONAN EXPRESSION IN THE DEVELOPMENT OF EXPERIMENTAL CRESCENTIC GLOMERULONEPHRITIS

CD44 is a widely expressed cell surface glycoprotein which is involved in both cell-matrix and cell-cell interactions which regulate a varie ty of processes, including leucocyte migration and activation. Therefo re, we examined the expression of CD44, and its major ligand hyalurona n, during the induction and progression of experimental glomerulonephr itis. Antibody staining of normal rat kidney showed constitutive CD44 expression by resident glomerular macrophages, parietal epithelial cel ls, medullary and occasional cortical tubules. There was a marked incr ease in CD44 expression over days 1, 7 and 21 of rat crescentic anti-g lomerular basement membrane (GBM) glomerulonephritis. Infiltrating mon ocytes and lymphocytes were CD44(+), with ultrastructural studies show ing high levels of CD44 expressed on the surface of lymphocytes adhere nt to activated endothelium. Marked hyaluronan deposition was seen in areas of fibrosis on days 7 and 21, such as glomerular crescents and t he periglomerular area. Hyaluronan deposition was accompanied by the p resence of many CD44(+) cells. Double immunohistochemistry showed that both CD44(+)ED1(+) macrophages and CD44(+) myofibroblasts (identified by expression of ct-smooth muscle actin) were present in areas of fib rosis. There was also a dramatic increase in cortical tubular CD44 exp ression, which was most evident in areas of tubular damage. Although t ubular epithelial cells expressed CD44 upon both the basolateral and l uminal surface, CD44 expression was most prominent within tight juncti ons, suggesting a role for CD44-CD44 interactions in cell-cell adhesio n within the tubule. Analysis of CD44 isoforms by reverse transcriptas e-polymerase chain reaction (RT-PCR) showed that the standard form of CD44 predominated in both normal and diseased kidney. However, a serie s of alternatively spliced CD44 isoforms was also detected, whose expr ession was markedly increased during disease. At least seven isoforms containing the v6 domain were identified, with the smallest form repre senting activated T cells. In conclusion, CD44 is constitutively expre ssed in normal kidney and is dramatically up-regulated in rat anti-GBM disease, suggesting possible roles for the CD44-hyaluronan interactio n in leucocyte recruitment, renal fibrosis and tubular cell-matrix and cell-cell interactions during the induction and progression of cresce ntic glomerulonephritis.