Schinner, Elisabeth and Wetzl, Veronika and Schramm, Andrea and Kees, Frieder and Sandner, Peter and Stasch, Johannes-Peter and Hofmann, Franz and Schlossmann, Jens (2017) Inhibition of the TGF beta signalling pathway by cGMP and cGMP-dependent kinase I in renal fibrosis. FEBS OPEN BIO, 7 (4). pp. 550-561. ISSN 2211-5463,
Full text not available from this repository. (Request a copy)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 TGFb 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/TGFb 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 plasminogenactivator 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | UNILATERAL URETERAL OBSTRUCTION; PLASMINOGEN-ACTIVATOR INHIBITOR-1; GROWTH-FACTOR; MATRIX METALLOPROTEINASES; PROTEIN; STIMULATION; DAMAGE; RELIEF; HYPERTENSION; PROGRESSION; cGMP-dependent protein kinase I; cyclic guanosine monophosphate; renal fibrosis; soluble guanylate cyclase stimulation |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmacology and Toxicology (Prof. Schlossmann, formerly Prof. Seifert) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Dec 2018 13:11 |
| Last Modified: | 12 Feb 2019 14:09 |
| URI: | https://pred.uni-regensburg.de/id/eprint/1090 |
Actions (login required)
 |
View Item |
