Abstract
Background. Endothelin-1 (ET-1) is involved in the progression of nephritis. Glomerular CD44 expression and the accumulation of its ligand hyaluronic acid (HA) both increase in nephritis. HA induces proliferation in many types of cells. We studied possible interactions among ET-1, CD44, and HA in mesangial cell (MC) proliferation, which contributes to the progression of nephritis. Methods. ET-1, CD44, proliferating cell nuclear antigen (PCNA), and HA immunohistochemistry were studied in renal lesions in MRL/MpJ-lpr/lpr (lpr/lpr) mice. The effects of ET-1, an endothelin-converting enzyme inhibitor, phosphoramidon, and an endothelin type-A (ETA) receptor antagonist, BQ-123, on CD44 expression and on HA-induced proliferation were studied in MC cultures. Results. Glomerular expression of ET-1 and CD44, and HA accumulation increased in nephritic lpr/lpr mice. Colocalization of areas positive for ET-1, CD44, and HA was observed, in part together with PCNA-positive nuclei in the glomeruli of the lpr/lpr mouse. ET-1 was secreted into MC culture medium. Phosphoramidon and BQ-123 suppressed the CD44 expression and HA-induced proliferation in MC culture, while the addition of ET-1 reversed the suppression of CD44 expression and the suppression of HA-induced proliferation by phosphoramidon. Conclusions. These results indicate that endogenously secreted ET-1 stimulates CD44 expression and HA-induced DNA synthesis via the ETA receptor. The increase in CD44 caused by ET-1 may be responsible for its stimulation of HA-induced DNA synthesis in MCs. These findings support the concept that interactions among ET-1, CD44, and HA promote MC proliferation, resulting in the progression of nephritis in lpr/lpr mice.
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