Cyclosporin A inhibits prostaglandin E2 formation by rat mesangial cells in culture.
A reversible reduction in glomerular filtration rate (GFR) is a frequent side effect in patients treated with the immunosuppressant cyclosporin A (CsA). The pathophysiology of acute CsA nephrotoxicity, however, is unclear. Since eicosanoids are local mediators of glomerular hemodynamics, they might be involved in CsA induced changes in GFR. We therefore studied the effect of CsA on prostaglandin E2 (PGE2) production by rat mesangial cells in culture. PGE2 production by mesangial cells following stimulation with angiotensin II (AII) (10(-6) M) or the Ca2+-ionophore A23187 (1 microgram/ml) was significantly inhibited when cells were grown for 24 hours in media which contained CsA (800 to 3200 ng/ml). CsA did not affect viability of mesangial cells as determined by 51Cr release or by cell proliferation measured by 3H-thymidine incorporation. CsA (3200 ng/ml) did not inhibit PGE2 formation by rat MC microsomes incubated with arachidonic acid. However, CsA, in a dose dependent manner, inhibited A23187 and angiotensin II induced release of 3H-labelled arachidonic acid from rat mesangial cells. These data demonstrate that CsA reduces PGE2 formation by rat mesangial cells in culture, probably by inhibiting the release of substrate arachidonic acid from cell membranes rather than by inhibition of cyclooxygenase. This effect may contribute to the reduction in GFR which accompanies CsA therapy.
Stahl
R A
RA
Department of Medicine, University of Washington, Seattle.
Adler
S
S
Baker
P J
PJ
Johnson
R J
RJ
Chen
Y P
YP
Pritzl
P
P
Couser
W G
WG
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D002478:Cells, Cultured; D002860:Chromium Radioisotopes; D003524:Cyclosporins / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D005920:Glomerular Mesangium / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D011458:Prostaglandins E / Q000096:biosynthesis*; D051381:Rats; D011919:Rats, Inbred Strains; D013936:Thymidine / Q000378:metabolism; D014316:Tritium
D001095:Arachidonic Acids; D002860:Chromium Radioisotopes; D003524:Cyclosporins; D011458:Prostaglandins E; D014316:Tritium; D000804:Angiotensin II; D016718:Arachidonic Acid; D000001:Calcimycin; D004247:DNA; D013936:Thymidine