Impact of PGE1 on cyclosporine A induced up-regulation of TGF-beta1, its receptors, and related matrix production in cultured mesangial cells.
Transforming growth factor-beta1 (TGF-beta1) plays a major role in cyclosporine A (CsA) induced glomerulosclerosis. We have recently shown that CsA up-regulates the expression of TGF-beta1 and its receptors type I (TbetaR-I) and type II (TbetaR-II) in rat mesangial cells (MCs). Prostaglandins of the E series (PGEs) are known to exert substantial anti-fibrotic effects. Here, we assessed the effect of PGE1 on CsA induced up-regulation of TGF-beta1, TbetaR-I, TbetaR-II and related matrix production in MCs. Co-incubation with PGE1 reduced CsA induced up-regulation of TGF-beta1 and TbetaR-II at the mRNA and protein level. Alike, PGE1 reduced TbetaR-I protein expression, which is posttranscriptionally up-regulated by CsA. Whereas a low PGE(1) concentration decreased CsA induced production of fibronectin (FN) and plasminogen activator inhibitor type-1 (PAI-1), a higher PGE1 concentration did not change FN production, but further increased PAI-1 production. In vivo studies will show, whether treatment with PGE1 analogues will be useful in preventing CsA induced glomerulosclerosis.
Dell
Kerstin
K
Department of Internal Medicine-Nephrology, University Hospital Charité, Campus Mitte, Humboldt-University, Schumannstrasse 20/21, 10117 Berlin, Germany.
Böhler
Torsten
T
Gaedeke
Jens
J
Budde
Klemens
K
Neumayer
Hans-Hellmut
HH
Waiser
Johannes
J
D000527:Alprostadil / Q000494:pharmacology*; D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D005353:Fibronectins / Q000187:drug effects; D005920:Glomerular Mesangium / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis; D051381:Rats; D018125:Receptors, Transforming Growth Factor beta / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000187:drug effects*
D005343:Fibrinolytic Agents; D005353:Fibronectins; D007166:Immunosuppressive Agents; D017395:Plasminogen Activator Inhibitor 1; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D016572:Cyclosporine; D000527:Alprostadil