Nitric oxide upregulates induction of PDGF receptor-alpha expression in rat renal mesangial cells and in anti-Thy-1 glomerulonephritis.
PDGF and nitric oxide (NO) have been shown to participate in the progression of several forms of glomerulonephritis. A potential influence of NO on PDGF-mediated signaling cascades was therefore examined. Treatment of rat mesangial cells (MC) with the NO donors diethylenetriamine NO (DETA-NO) or spermine-NONOate resulted in a time- and dose-dependent upregulation of PDGF receptor alpha (PDGFRalpha) but not PDGFRbeta mRNA levels. Administration of DETA-NO also induced PDGFRalpha protein expression that was paralleled also by an enhanced receptor phosphorylation. Further experiments using 3-(5-hydroxymethyl-2-furyl)-1-benzylindazole (YC-1), an activator of the soluble guanylyl cyclase (sGC), the membrane-soluble cyclic GMP (cGMP) analog 8-Bromo-PET-cGMP, and the inhibitors of sGC ODQ and NS2028 suggest that elevated cGMP levels are responsible for the effects of NO. Importantly, NO-dependent autophosphorylation of PDGFRalpha drastically augmented PDGF-AA-evoked phosphorylation of PKB/Akt, a classical downstream target of PDGFRalpha signaling. Furthermore, in a rat model of anti-Thy-1 glomerulonephritis, expression and phosphorylation of PDGFRalpha but not PDGFRbeta expression was markedly reduced in nephritic animals that were treated with the inducible NO synthase inhibitor L-N6(1-iminoethyl)lysine(dihydrochloride) (L-NIL) compared with non-L-NIL-treated nephritic rats as demonstrated by Western blotting and immunohistochemistry. Taken together, the data suggest that NO modulates PDGFRalpha-triggered signaling in a cGMP-dependent manner by induction of PDGFRalpha expression in MC and in a rat model of mesangioproliferative glomerulonephritis. The mechanistic details of this regulation have to be elucidated in further experiments.
Beck
Karl-Friedrich
KF
Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe Universität Frankfurt am Main, Theodor-Stern-Kai 7, D-60590, Frankfurt am Main, Germany. k.f.beck@em.uni-frankfurt.de
Güder
Gülmisal
G
Schaefer
Liliana
L
Pleskova
Miriam
M
Babelova
Andrea
A
Behrens
Meik H
MH
Mihalik
Daniel
D
Beck
Martina
M
Schaefer
Roland M
RM
Pfeilschifter
Josef
J
D000818:Animals; D002478:Cells, Cultured; D005920:Glomerular Mesangium / Q000378:metabolism* / Q000503:physiopathology; D005921:Glomerulonephritis / Q000276:immunology / Q000503:physiopathology*; D007518:Isoantibodies / Q000276:immunology*; D023421:Models, Animal; D009569:Nitric Oxide / Q000502:physiology*; D051381:Rats; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000096:biosynthesis*; D015854:Up-Regulation
D007518:Isoantibodies; C035678:anti-Thy antibody; D009569:Nitric Oxide; D020796:Receptor, Platelet-Derived Growth Factor alpha