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- Title
Inhibition of the TGFβ signalling pathway by cGMP and cGMP-dependent kinase I in renal fibrosis.
- Authors
Schinner, Elisabeth; Wetzl, Veronika; Schramm, Andrea; Kees, Frieder; Sandner, Peter; Stasch, Johannes-Peter; Hofmann, Franz; Schlossmann, Jens
- Abstract
Agents that enhance production of nitric oxide ( NO) and cyclic guanosine monophosphate ( cGMP) ameliorate the progression of renal fibrosis. However, the molecular mechanism of this process is not fully understood. We hypothesize that the antifibrotic effects of cGMP and cGMP-dependent kinase I ( cGKI) are mediated via regulation of the TGFβ signalling pathway, both via ERK and the Smad-dependent route. Kidney fibrosis was induced by unilateral ureter obstruction ( UUO) in wild-type and cGKI-deficient ( cGKI- KO) mice. The cGMP/ cGKI signalling pathway was activated by application of the soluble guanylate cyclase ( sGC) stimulator BAY 41-8543 ( BAY), beginning 1 day after UUO. After 7 days, the antifibrotic effects of BAY were analysed by measuring mRNA and protein expression of characteristic fibrotic biomarkers. The effects of cGMP/ TGFβ on cultured fibroblasts were also analysed in vitro. BAY application influenced the activity of the extracellular matrix ( ECM)-degrading matrix metalloproteases ( MMP2 and MMP9) and their inhibitor tissue inhibitors of metalloproteinase-1, the secretion of cytokines (e.g. IL-6) and the expression pattern of ECM proteins (e.g. collagen, fibronectin) and profibrotic mediators (e.g. connective tissue growth factors and plasminogen-activator inhibitor-1). Activation of the cGMP/ cGKI signalling pathway showed protective effects against fibrosis which were mediated by inhibition of P-Erk1/2 and translocation of P-smad3. The elucidation of these signalling mechanisms might support the development of new therapeutic options regarding cGMP/ cGKI-mediated antifibrotic actions.
- Subjects
TRANSFORMING growth factors; CELL communication; CGMP-dependent protein kinase; RENAL fibrosis; CELLULAR control mechanisms; GUANYLATE cyclase
- Publication
FEBS Open Bio, 2017, Vol 7, Issue 4, p550
- ISSN
2211-5463
- Publication type
Article
- DOI
10.1002/2211-5463.12202