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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

Serum creatinine levels in healthy mice or 7 days after UUO in WT and cGKI-KO mice. Serum creatinine levels were determined via high pressure liquid chromatography as described in methods. cGKI, cGMP-dependent protein kinase I; KO, knock out; RLX, serelaxin; WT, wildtype, ∗p < 0.05.
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Figure 7: Serum creatinine levels in healthy mice or 7 days after UUO in WT and cGKI-KO mice. Serum creatinine levels were determined via high pressure liquid chromatography as described in methods. cGKI, cGMP-dependent protein kinase I; KO, knock out; RLX, serelaxin; WT, wildtype, ∗p < 0.05.

Mentions: Kidney function was measured by serum creatinine levels analyzed 7 days after UUO. Figure 7 shows that serum creatinine increased significantly after UUO, but renal performance improved significantly through RLX treatment by reducing serum creatinine levels from 1.0 mg/l ± 0.049 to 0.80 mg/l ± 0.069 in WT. cGKI-KO did not improve kidney function through RLX.


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)

Serum creatinine levels in healthy mice or 7 days after UUO in WT and cGKI-KO mice. Serum creatinine levels were determined via high pressure liquid chromatography as described in methods. cGKI, cGMP-dependent protein kinase I; KO, knock out; RLX, serelaxin; WT, wildtype, ∗p < 0.05.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 7: Serum creatinine levels in healthy mice or 7 days after UUO in WT and cGKI-KO mice. Serum creatinine levels were determined via high pressure liquid chromatography as described in methods. cGKI, cGMP-dependent protein kinase I; KO, knock out; RLX, serelaxin; WT, wildtype, ∗p < 0.05.
Mentions: Kidney function was measured by serum creatinine levels analyzed 7 days after UUO. Figure 7 shows that serum creatinine increased significantly after UUO, but renal performance improved significantly through RLX treatment by reducing serum creatinine levels from 1.0 mg/l ± 0.049 to 0.80 mg/l ± 0.069 in WT. cGKI-KO did not improve kidney function through RLX.

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