Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Huang, J.S. et al.

Huang, Chuang, Guh, Chen, Yang, Chiang, Hung, Liao,

Effect of nitric oxide-cGMP-dependent protein kinase activation on advanced glycation end-product-induced proliferation in renal fibroblasts.

Renal interstitial fibrosis is believed to play a key role in the development of diabetic nephropathy (DN), and advanced glycation end-products (AGE) may contribute importantly to this. Recent reports have shown that nitric oxide (NO) is closely linked to the renal interstitial fibrosis of DN. In this study, the mechanisms by which NO and its downstream signals mediate the AGE-induced proliferative response in normal rat kidney fibroblasts (NRK-49F) are examined. AGE decreased NO production, cyclic guanosine 5'monophosphate (cGMP) synthesis, and cGMP-dependent protein kinase (PKG) activation time- and dose-dependently. These effects were not observed when cells were treated with nonglycated BSA. NO and inducible nitric oxide synthase (iNOS) stimulated by NO donors S-nitroso-N-acetylpenicillamine (SNAP)/sodium nitroprusside (SNP) and PKG activator 8-para-chlorophenylthio-cGMP (8-pCPT-cGMP) prevented both AGE- induced proliferation and Janus kinase 2 (JAK2)-signal transducers and activators of transcription 5 (STAT5) activation but not p42/p44 mitogen- activated protein kinase ( MAPK) activation. The ability of NO-PKG to inhibit AGE-induced cell cycle progression was verified by the observation that SNAP, SNP, and 8-pCPT-cGMP inhibited both cyclin D1 and cdk4 activation. Furthermore, induction of NO-PKG significantly increased p21Waf1/Cip1 expression in AGE-treated NRK-49F cells. The data suggest that the NO-PKG pathway inhibits AGE-induced proliferation by suppressing activation of JAK2-STAT5 and cyclin D1/cdk4 and induction of p21Waf1/Cip1.[1]

References

Effect of nitric oxide-cGMP-dependent protein kinase activation on advanced glycation end-product-induced proliferation in renal fibroblasts. Huang, J.S., Chuang, L.Y., Guh, J.Y., Chen, C.J., Yang, Y.L., Chiang, T.A., Hung, M.Y., Liao, T.N. J. Am. Soc. Nephrol. (2005) [Pubmed]

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