title: Inhibition of the TGFβ signalling pathway by cGMP and cGMP-dependent kinase I in renal fibrosis.
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 analysedin 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.
authors.affiliation: Department of Pharmacology and Toxicology University of Regensburg Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Schinner
authors.affiliation: Department of Pharmacology and Toxicology University of Regensburg Germany; Novartis Pharma GmbH Nuremberg Germany.
authors.forename: Veronika
authors.initials: V
authors.lastname: Wetzl
authors.affiliation: Department of Pharmacology and Toxicology University of Regensburg Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schramm
authors.affiliation: Department of Pharmacology and Toxicology University of Regensburg Germany.
authors.forename: Frieder
authors.initials: F
authors.lastname: Kees
authors.affiliation: Bayer Pharma AG Wuppertal Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Sandner
authors.affiliation: Institute of Pharmacology and Toxicology Technical University of Munich Germany.
authors.forename: Johannes-Peter
authors.initials: JP
authors.lastname: Stasch
authors.affiliation: Institute of Pharmacology and Toxicology Technical University of Munich Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Hofmann
authors.affiliation: Department of Pharmacology and Toxicology University of Regensburg Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Schlossmann
keywords: cGMP‐dependent protein kinase I; cyclic guanosine monophosphate; renal fibrosis; soluble guanylate cyclase stimulation