AJP - Cell Physiology, Vol 263, Issue 1 C200-C209, Copyright © 1992 by American Physiological Society
Sustained activation of PGE2 synthesis in mesangial cells cocultured with glomerular endothelial cells
K. Uchida and B. J. Ballermann
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Glomerular endothelial cells synthesize and release endothelin-1 (ET-1),
and mesangial cells, normally closely apposed to endothelial cells in vivo,
respond to ET-1 with contraction, proliferation, and prostaglandin E2
(PGE2) release. This study sought to determine whether chronic coculture of
mesangial cells with glomerular endothelial cells alters mesangial cell
PGE2 synthesis. Mesangial cells cocultured with endothelial cells were
found to release PGE2 at rates much greater than those observed in
mesangial cells not cocultured with endothelial cells. This effect
persisted for at least 24 h after the mesangial cells were removed from
coculture with endothelial cells. The increase in basal mesangial cell PGE2
synthesis was dependent on endothelial cell-derived ET-1. Despite the
increase in basal PGE2 synthesis after coculture with endothelial cells,
acute ET-1-stimulated PGE2 release was markedly blunted in mesangial cells
that had been cocultured with endothelial cells when compared with
mesangial cells in solo-culture. This lack of responsiveness was specific
for ET-1 and resulted from a profound downregulation of mesangial cell
endothelin receptors. Thus coculture with endothelial cells produces two
apparently opposing and ET-1-dependent effects in mesangial cells, namely a
sustained increase in basal PGE2 synthesis by the cells and a loss of
responsiveness to further stimulation with ET-1. It is postulated that the
induction of sustained PGE2 synthesis may also occur in vivo if endothelin
release from endothelial cells is stimulated and may explain, in part, the
extraordinary sensitivity of some patients with glomerular disease to
cyclooxygenase inhibitors.
