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Nitric Oxide Upregulates Induction of PDGF Receptor- Expression in Rat Renal Mesangial Cells and in Anti-Thy-1 Glomerulonephritis

Karl-Friedrich Beck^*, Gülmisal Güder^*, Liliana Schaefer, Miriam Pleskova^*, Andrea Babelova, Meik H. Behrens^*, Daniel Mihalik, Martina Beck^*, Roland M. Schaefer and Josef Pfeilschifter^*

^* Pharmazentrum Frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe Universität, Frankfurt am Main, Germany; and Abteilung für Innere Medizin D, Universität Münster, Münster, Germany

Address correspondence to: Dr. Karl-Friedrich Beck, Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe Universität Frankfurt am Main, Theodor-Stern-Kai 7, D-60590, Frankfurt am Main, Germany. Phone: +49-69-6301-6953; Fax: +49-6301-7942; E-mail: k.f.beck{at}em.uni-frankfurt.de

Received for publication August 4, 2004. Accepted for publication March 9, 2005.

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 (PDGFR) but not PDGFR mRNA levels. Administration of DETA-NO also induced PDGFR 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 PDGFR drastically augmented PDGF-AA–evoked phosphorylation of PKB/Akt, a classical downstream target of PDGFR signaling. Furthermore, in a rat model of anti-Thy-1 glomerulonephritis, expression and phosphorylation of PDGFR but not PDGFR 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 PDGFR-triggered signaling in a cGMP-dependent manner by induction of PDGFR expression in MC and in a rat model of mesangioproliferative glomerulonephritis. The mechanistic details of this regulation have to be elucidated in further experiments.

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673