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

Nitric Oxide Upregulates Induction of PDGF Receptor-Alpha 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, Josef Pfeilschifter

J Am Soc Nephrol. 2005 Jul;16(7):1948-57.

PMID: 15872077

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP159190451	L-N6-(1-Iminoethyl)lysine dihydrochloride		159190-45-1	Price

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