Wetzl, Veronika and Schinner, Elisabeth and Kees, Frieder and Hofmann, Franz and Faerber, Lothar and Schlossmann, Jens (2016) Involvement of Cyclic Guanosine Monophosphate-Dependent Protein Kinase I in Renal Antifibrotic Effects of Serelaxin. FRONTIERS IN PHARMACOLOGY, 7: UNSP 195. ISSN 1663-9812,
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Introduction: Kidney fibrosis has shown to be ameliorated through the involvement of cyclic guanosine monophosphate (cGMP) and its dependent protein kinase I (cGKI). Serelaxin, the recombinant form of human relaxin-II, increases cGMP levels and has shown beneficial effects on kidney function in acute heart failure patients. Antifibrotic properties of serelaxin are supposed to be mediated via relaxin family peptide receptor 1 and subsequently enhanced nitric oxide/ cGMP to inhibit transforming growth factor 1)) (TGFI)) signaling. This study examines the involvement of cGKI in the antifibrotic signaling of serelaxin. Methods and Results: Kidney fibrosis was induced by unilateral ureteral obstruction in wildtype (WT) and cGKI knock-out (KO) mice. After 7 days, renal antifibrotic effects of serelaxin were assessed. Serelaxin treatment for 7 days significantly increased cGMP in the kidney of WT and cGKI-KO. In WT, renal fibrosis was reduced through decreased accumulation of collagenl A1, total collagen, and fibronectin. The profibrotic connective tissue growth factor as well as myofibroblast differentiation were reduced and matrix metalloproteinases-2 and-9 were positively modulated after treatment. Moreover, Smad2 as well as extracellular signal-regulated kinase 1 (ERK1) phosphorylation were decreased, whereas phosphodiesterase (PDE) 5a phosphorylation was increased. However, these effects were not observed in cGKI-KO. Conclusion: Antifibrotic renal effects of serelaxin are mediated via cGMP/cGKI to inhibit Smad2- and ERK1-dependent TGF-13 signaling and increased PDE5a phosphorylation.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | UNILATERAL URETERAL OBSTRUCTION; RELAXIN FAMILY PEPTIDES; TISSUE GROWTH-FACTOR; INTERSTITIAL FIBROSIS; NITRIC-OXIDE; TGF-BETA; TUBULOINTERSTITIAL FIBROSIS; HEART-FAILURE; MATRIX METALLOPROTEINASES; HYPERTENSIVE-RATS; Relaxin; serelaxin; cGMP-dependent protein kinase; kidney; interstitial fibrosis; signaling; nitric oxide |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy Chemistry and Pharmacy > Institute of Pharmacy > Pharmacology and Toxicology (Prof. Schlossmann, formerly Prof. Seifert) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 29 Mar 2019 12:17 |
| Last Modified: | 29 Mar 2019 12:17 |
| URI: | https://pred.uni-regensburg.de/id/eprint/3632 |
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