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Involvement of Cyclic Guanosine Monophosphate-Dependent Protein Kinase I in Renal Antifibrotic Effects of Serelaxin.

Wetzl V, Schinner E, Kees F, Hofmann F, Faerber L, Schlossmann J - Front Pharmacol (2016)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, University of RegensburgRegensburg, Germany; Novartis Pharma GmbHNuremberg, Germany.

ABSTRACT

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-β (TGF-β) 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 collagen1A1, 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-β signaling and increased PDE5a phosphorylation.

No MeSH data available.


Related in: MedlinePlus

Proposed hypothesis for in vivo antifibrotic signaling pathway of serelaxin in kidney. Serelaxin mediates its antifibrotic effect via RXFP1/cGMP/cGKI to inhibit TGF-β dependent Smad- and ERK-phosphorylation, which subsequently decreases ECM accumulation and suppresses profibrotic stimuli; α-SMA, α-smooth muscle actin; cGKI, cGMP-dependent protein kinase I; cGMP, cyclic guanosine monophosphate; CTGF, connective tissue growth factor; ECM, extracellular matrix; ERK, extracellular-signal regulated kinase; GMP, guanosine monophosphate; MMPs, matrix metalloproteinases; PDE5a, phosphodiesterase 5a; RXFP1, relaxin family peptide receptor 1; Smad, small mothers against decapentaplegic protein; TGF-β, transforming growth factor-β.
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Figure 8: Proposed hypothesis for in vivo antifibrotic signaling pathway of serelaxin in kidney. Serelaxin mediates its antifibrotic effect via RXFP1/cGMP/cGKI to inhibit TGF-β dependent Smad- and ERK-phosphorylation, which subsequently decreases ECM accumulation and suppresses profibrotic stimuli; α-SMA, α-smooth muscle actin; cGKI, cGMP-dependent protein kinase I; cGMP, cyclic guanosine monophosphate; CTGF, connective tissue growth factor; ECM, extracellular matrix; ERK, extracellular-signal regulated kinase; GMP, guanosine monophosphate; MMPs, matrix metalloproteinases; PDE5a, phosphodiesterase 5a; RXFP1, relaxin family peptide receptor 1; Smad, small mothers against decapentaplegic protein; TGF-β, transforming growth factor-β.

Mentions: In this study, we demonstrated that RLX mediated its antifibrotic effects via NO/cGMP/cGKI, to inhibit TGF-β signaling through Smad- and ERK1-dependent pathways (Figure 8).


Involvement of Cyclic Guanosine Monophosphate-Dependent Protein Kinase I in Renal Antifibrotic Effects of Serelaxin.

Wetzl V, Schinner E, Kees F, Hofmann F, Faerber L, Schlossmann J - Front Pharmacol (2016)

Proposed hypothesis for in vivo antifibrotic signaling pathway of serelaxin in kidney. Serelaxin mediates its antifibrotic effect via RXFP1/cGMP/cGKI to inhibit TGF-β dependent Smad- and ERK-phosphorylation, which subsequently decreases ECM accumulation and suppresses profibrotic stimuli; α-SMA, α-smooth muscle actin; cGKI, cGMP-dependent protein kinase I; cGMP, cyclic guanosine monophosphate; CTGF, connective tissue growth factor; ECM, extracellular matrix; ERK, extracellular-signal regulated kinase; GMP, guanosine monophosphate; MMPs, matrix metalloproteinases; PDE5a, phosphodiesterase 5a; RXFP1, relaxin family peptide receptor 1; Smad, small mothers against decapentaplegic protein; TGF-β, transforming growth factor-β.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4940422&req=5

Figure 8: Proposed hypothesis for in vivo antifibrotic signaling pathway of serelaxin in kidney. Serelaxin mediates its antifibrotic effect via RXFP1/cGMP/cGKI to inhibit TGF-β dependent Smad- and ERK-phosphorylation, which subsequently decreases ECM accumulation and suppresses profibrotic stimuli; α-SMA, α-smooth muscle actin; cGKI, cGMP-dependent protein kinase I; cGMP, cyclic guanosine monophosphate; CTGF, connective tissue growth factor; ECM, extracellular matrix; ERK, extracellular-signal regulated kinase; GMP, guanosine monophosphate; MMPs, matrix metalloproteinases; PDE5a, phosphodiesterase 5a; RXFP1, relaxin family peptide receptor 1; Smad, small mothers against decapentaplegic protein; TGF-β, transforming growth factor-β.
Mentions: In this study, we demonstrated that RLX mediated its antifibrotic effects via NO/cGMP/cGKI, to inhibit TGF-β signaling through Smad- and ERK1-dependent pathways (Figure 8).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, University of RegensburgRegensburg, Germany; Novartis Pharma GmbHNuremberg, Germany.

ABSTRACT

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-β (TGF-β) 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 collagen1A1, 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-β signaling and increased PDE5a phosphorylation.

No MeSH data available.


Related in: MedlinePlus