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Veronika Wetzl - One of the best experts on this subject based on the ideXlab platform.
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Differences in the renal Antifibrotic cGMP/cGKI-dependent signaling of serelaxin, zaprinast, and their combination
Naunyn-Schmiedeberg's Archives of Pharmacology, 2017Co-Authors: Veronika Wetzl, Elisabeth Schinner, Lothar Faerber, Frieder Kees, Jens SchlossmannAbstract:Renal fibrosis is an important factor for end-stage renal failure. However, only few therapeutic options for its treatment are established. Zaprinast, a phosphodiesterase 5 inhibitor, and serelaxin, the recombinant form of the naturally occurring hormone relaxin, are differently acting modulators of cyclic guanosine monophosphate (cGMP) signaling. Both agents enhance cGMP availability in kidney tissue. These substances alone or in combination might interfere with the development of kidney fibrosis. Therefore, we compared the effects of combination therapy with the effects of monotherapy on renal fibrosis. Renal fibrosis was induced by unilateral ureteral obstruction (UUO) for 7 days in wild-type (WT) and cGKI knockout (KO) mice. Renal Antifibrotic effects were assessed after 7 days. In WT, zaprinast and the combination of zaprinast and serelaxin significantly reduced renal interstitial fibrosis assessed by α-SMA, fibronectin, collagen1A1, and gelatinases (MMP2 and MMP9). Intriguingly in cGKI-KO, mRNA and protein expression of fibronectin and collagen1A1 were reduced by zaprinast, in contrast to serelaxin. Gelatinases are not regulated by zaprinast. Although both substances showed similar Antifibrotic properties in WT, they distinguished in their effect mechanisms. In contrast to serelaxin which acts both on Smad2 and Erk1, zaprinast did not significantly diminish Erk1/2 phosphorylation. Interestingly, the combination of serelaxin/zaprinast achieved no additive Antifibrotic effects compared to the monotherapy. Due to Antifibrotic effects of zaprinast in cGKI-KO, we hypothesize that additional cGKI-independent mechanisms are supposed for Antifibrotic signaling of zaprinast.
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differences in the renal Antifibrotic cgmp cgki dependent signaling of serelaxin zaprinast and their combination
Naunyn-schmiedebergs Archives of Pharmacology, 2017Co-Authors: Veronika Wetzl, Elisabeth Schinner, Lothar Faerber, Frieder Kees, Jens SchlossmannAbstract:Renal fibrosis is an important factor for end-stage renal failure. However, only few therapeutic options for its treatment are established. Zaprinast, a phosphodiesterase 5 inhibitor, and serelaxin, the recombinant form of the naturally occurring hormone relaxin, are differently acting modulators of cyclic guanosine monophosphate (cGMP) signaling. Both agents enhance cGMP availability in kidney tissue. These substances alone or in combination might interfere with the development of kidney fibrosis. Therefore, we compared the effects of combination therapy with the effects of monotherapy on renal fibrosis. Renal fibrosis was induced by unilateral ureteral obstruction (UUO) for 7 days in wild-type (WT) and cGKI knockout (KO) mice. Renal Antifibrotic effects were assessed after 7 days. In WT, zaprinast and the combination of zaprinast and serelaxin significantly reduced renal interstitial fibrosis assessed by α-SMA, fibronectin, collagen1A1, and gelatinases (MMP2 and MMP9). Intriguingly in cGKI-KO, mRNA and protein expression of fibronectin and collagen1A1 were reduced by zaprinast, in contrast to serelaxin. Gelatinases are not regulated by zaprinast. Although both substances showed similar Antifibrotic properties in WT, they distinguished in their effect mechanisms. In contrast to serelaxin which acts both on Smad2 and Erk1, zaprinast did not significantly diminish Erk1/2 phosphorylation. Interestingly, the combination of serelaxin/zaprinast achieved no additive Antifibrotic effects compared to the monotherapy. Due to Antifibrotic effects of zaprinast in cGKI-KO, we hypothesize that additional cGKI-independent mechanisms are supposed for Antifibrotic signaling of zaprinast.
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involvement of cyclic guanosine monophosphate dependent protein kinase i in renal Antifibrotic effects of serelaxin
Frontiers in Pharmacology, 2016Co-Authors: Veronika Wetzl, Elisabeth Schinner, Lothar Faerber, Frieder Kees, Franz Hofmann, Jens SchlossmannAbstract: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 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 ureter 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 CTGF 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.
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Differences in the renal Antifibrotic signaling of serelaxin and zaprinast.
BMC Clinical Pharmacology, 2015Co-Authors: Veronika Wetzl, Elisabeth Schinner, Lothar Faerber, Franz Hofmann, Jens SchlossmannAbstract:Background Kidney fibrosis is frequently observed in cardiorenal diseases. Cyclic guanosine monophosphate (cGMP) serves as the most important second messenger of nitric oxide (NO) and has shown Antifibrotic effects at enhanced levels in several experimental models of kidney diseases. Antifibrotic effects of cGMP signalling via cGMP-dependent protein kinases (cGK), in particular cGKI, have already been shown. Serelaxin and zaprinast are both able to increase cGMP signalling via influencing two independent pharmacological targets. Serelaxin is currently in phase III development for acute heart failure and has shown Antifibrotic properties in several in vitro and in vivo experiments. It is discussed that serelaxin inhibits TGF-b signalling via RXFP1 receptor. Involvement of NO / cGMP in this process has also been revealed. Zaprinast is a selective inhibitor of phosphodiesterase V, which leads to enhanced levels of cGMP by blocking cGMP degradation.
Jens Schlossmann - One of the best experts on this subject based on the ideXlab platform.
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Differences in the renal Antifibrotic cGMP/cGKI-dependent signaling of serelaxin, zaprinast, and their combination
Naunyn-Schmiedeberg's Archives of Pharmacology, 2017Co-Authors: Veronika Wetzl, Elisabeth Schinner, Lothar Faerber, Frieder Kees, Jens SchlossmannAbstract:Renal fibrosis is an important factor for end-stage renal failure. However, only few therapeutic options for its treatment are established. Zaprinast, a phosphodiesterase 5 inhibitor, and serelaxin, the recombinant form of the naturally occurring hormone relaxin, are differently acting modulators of cyclic guanosine monophosphate (cGMP) signaling. Both agents enhance cGMP availability in kidney tissue. These substances alone or in combination might interfere with the development of kidney fibrosis. Therefore, we compared the effects of combination therapy with the effects of monotherapy on renal fibrosis. Renal fibrosis was induced by unilateral ureteral obstruction (UUO) for 7 days in wild-type (WT) and cGKI knockout (KO) mice. Renal Antifibrotic effects were assessed after 7 days. In WT, zaprinast and the combination of zaprinast and serelaxin significantly reduced renal interstitial fibrosis assessed by α-SMA, fibronectin, collagen1A1, and gelatinases (MMP2 and MMP9). Intriguingly in cGKI-KO, mRNA and protein expression of fibronectin and collagen1A1 were reduced by zaprinast, in contrast to serelaxin. Gelatinases are not regulated by zaprinast. Although both substances showed similar Antifibrotic properties in WT, they distinguished in their effect mechanisms. In contrast to serelaxin which acts both on Smad2 and Erk1, zaprinast did not significantly diminish Erk1/2 phosphorylation. Interestingly, the combination of serelaxin/zaprinast achieved no additive Antifibrotic effects compared to the monotherapy. Due to Antifibrotic effects of zaprinast in cGKI-KO, we hypothesize that additional cGKI-independent mechanisms are supposed for Antifibrotic signaling of zaprinast.
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differences in the renal Antifibrotic cgmp cgki dependent signaling of serelaxin zaprinast and their combination
Naunyn-schmiedebergs Archives of Pharmacology, 2017Co-Authors: Veronika Wetzl, Elisabeth Schinner, Lothar Faerber, Frieder Kees, Jens SchlossmannAbstract:Renal fibrosis is an important factor for end-stage renal failure. However, only few therapeutic options for its treatment are established. Zaprinast, a phosphodiesterase 5 inhibitor, and serelaxin, the recombinant form of the naturally occurring hormone relaxin, are differently acting modulators of cyclic guanosine monophosphate (cGMP) signaling. Both agents enhance cGMP availability in kidney tissue. These substances alone or in combination might interfere with the development of kidney fibrosis. Therefore, we compared the effects of combination therapy with the effects of monotherapy on renal fibrosis. Renal fibrosis was induced by unilateral ureteral obstruction (UUO) for 7 days in wild-type (WT) and cGKI knockout (KO) mice. Renal Antifibrotic effects were assessed after 7 days. In WT, zaprinast and the combination of zaprinast and serelaxin significantly reduced renal interstitial fibrosis assessed by α-SMA, fibronectin, collagen1A1, and gelatinases (MMP2 and MMP9). Intriguingly in cGKI-KO, mRNA and protein expression of fibronectin and collagen1A1 were reduced by zaprinast, in contrast to serelaxin. Gelatinases are not regulated by zaprinast. Although both substances showed similar Antifibrotic properties in WT, they distinguished in their effect mechanisms. In contrast to serelaxin which acts both on Smad2 and Erk1, zaprinast did not significantly diminish Erk1/2 phosphorylation. Interestingly, the combination of serelaxin/zaprinast achieved no additive Antifibrotic effects compared to the monotherapy. Due to Antifibrotic effects of zaprinast in cGKI-KO, we hypothesize that additional cGKI-independent mechanisms are supposed for Antifibrotic signaling of zaprinast.
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involvement of cyclic guanosine monophosphate dependent protein kinase i in renal Antifibrotic effects of serelaxin
Frontiers in Pharmacology, 2016Co-Authors: Veronika Wetzl, Elisabeth Schinner, Lothar Faerber, Frieder Kees, Franz Hofmann, Jens SchlossmannAbstract: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 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 ureter 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 CTGF 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.
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Differences in the renal Antifibrotic signaling of serelaxin and zaprinast.
BMC Clinical Pharmacology, 2015Co-Authors: Veronika Wetzl, Elisabeth Schinner, Lothar Faerber, Franz Hofmann, Jens SchlossmannAbstract:Background Kidney fibrosis is frequently observed in cardiorenal diseases. Cyclic guanosine monophosphate (cGMP) serves as the most important second messenger of nitric oxide (NO) and has shown Antifibrotic effects at enhanced levels in several experimental models of kidney diseases. Antifibrotic effects of cGMP signalling via cGMP-dependent protein kinases (cGK), in particular cGKI, have already been shown. Serelaxin and zaprinast are both able to increase cGMP signalling via influencing two independent pharmacological targets. Serelaxin is currently in phase III development for acute heart failure and has shown Antifibrotic properties in several in vitro and in vivo experiments. It is discussed that serelaxin inhibits TGF-b signalling via RXFP1 receptor. Involvement of NO / cGMP in this process has also been revealed. Zaprinast is a selective inhibitor of phosphodiesterase V, which leads to enhanced levels of cGMP by blocking cGMP degradation.
Lothar Faerber - One of the best experts on this subject based on the ideXlab platform.
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Differences in the renal Antifibrotic cGMP/cGKI-dependent signaling of serelaxin, zaprinast, and their combination
Naunyn-Schmiedeberg's Archives of Pharmacology, 2017Co-Authors: Veronika Wetzl, Elisabeth Schinner, Lothar Faerber, Frieder Kees, Jens SchlossmannAbstract:Renal fibrosis is an important factor for end-stage renal failure. However, only few therapeutic options for its treatment are established. Zaprinast, a phosphodiesterase 5 inhibitor, and serelaxin, the recombinant form of the naturally occurring hormone relaxin, are differently acting modulators of cyclic guanosine monophosphate (cGMP) signaling. Both agents enhance cGMP availability in kidney tissue. These substances alone or in combination might interfere with the development of kidney fibrosis. Therefore, we compared the effects of combination therapy with the effects of monotherapy on renal fibrosis. Renal fibrosis was induced by unilateral ureteral obstruction (UUO) for 7 days in wild-type (WT) and cGKI knockout (KO) mice. Renal Antifibrotic effects were assessed after 7 days. In WT, zaprinast and the combination of zaprinast and serelaxin significantly reduced renal interstitial fibrosis assessed by α-SMA, fibronectin, collagen1A1, and gelatinases (MMP2 and MMP9). Intriguingly in cGKI-KO, mRNA and protein expression of fibronectin and collagen1A1 were reduced by zaprinast, in contrast to serelaxin. Gelatinases are not regulated by zaprinast. Although both substances showed similar Antifibrotic properties in WT, they distinguished in their effect mechanisms. In contrast to serelaxin which acts both on Smad2 and Erk1, zaprinast did not significantly diminish Erk1/2 phosphorylation. Interestingly, the combination of serelaxin/zaprinast achieved no additive Antifibrotic effects compared to the monotherapy. Due to Antifibrotic effects of zaprinast in cGKI-KO, we hypothesize that additional cGKI-independent mechanisms are supposed for Antifibrotic signaling of zaprinast.
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differences in the renal Antifibrotic cgmp cgki dependent signaling of serelaxin zaprinast and their combination
Naunyn-schmiedebergs Archives of Pharmacology, 2017Co-Authors: Veronika Wetzl, Elisabeth Schinner, Lothar Faerber, Frieder Kees, Jens SchlossmannAbstract:Renal fibrosis is an important factor for end-stage renal failure. However, only few therapeutic options for its treatment are established. Zaprinast, a phosphodiesterase 5 inhibitor, and serelaxin, the recombinant form of the naturally occurring hormone relaxin, are differently acting modulators of cyclic guanosine monophosphate (cGMP) signaling. Both agents enhance cGMP availability in kidney tissue. These substances alone or in combination might interfere with the development of kidney fibrosis. Therefore, we compared the effects of combination therapy with the effects of monotherapy on renal fibrosis. Renal fibrosis was induced by unilateral ureteral obstruction (UUO) for 7 days in wild-type (WT) and cGKI knockout (KO) mice. Renal Antifibrotic effects were assessed after 7 days. In WT, zaprinast and the combination of zaprinast and serelaxin significantly reduced renal interstitial fibrosis assessed by α-SMA, fibronectin, collagen1A1, and gelatinases (MMP2 and MMP9). Intriguingly in cGKI-KO, mRNA and protein expression of fibronectin and collagen1A1 were reduced by zaprinast, in contrast to serelaxin. Gelatinases are not regulated by zaprinast. Although both substances showed similar Antifibrotic properties in WT, they distinguished in their effect mechanisms. In contrast to serelaxin which acts both on Smad2 and Erk1, zaprinast did not significantly diminish Erk1/2 phosphorylation. Interestingly, the combination of serelaxin/zaprinast achieved no additive Antifibrotic effects compared to the monotherapy. Due to Antifibrotic effects of zaprinast in cGKI-KO, we hypothesize that additional cGKI-independent mechanisms are supposed for Antifibrotic signaling of zaprinast.
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involvement of cyclic guanosine monophosphate dependent protein kinase i in renal Antifibrotic effects of serelaxin
Frontiers in Pharmacology, 2016Co-Authors: Veronika Wetzl, Elisabeth Schinner, Lothar Faerber, Frieder Kees, Franz Hofmann, Jens SchlossmannAbstract: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 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 ureter 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 CTGF 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.
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Differences in the renal Antifibrotic signaling of serelaxin and zaprinast.
BMC Clinical Pharmacology, 2015Co-Authors: Veronika Wetzl, Elisabeth Schinner, Lothar Faerber, Franz Hofmann, Jens SchlossmannAbstract:Background Kidney fibrosis is frequently observed in cardiorenal diseases. Cyclic guanosine monophosphate (cGMP) serves as the most important second messenger of nitric oxide (NO) and has shown Antifibrotic effects at enhanced levels in several experimental models of kidney diseases. Antifibrotic effects of cGMP signalling via cGMP-dependent protein kinases (cGK), in particular cGKI, have already been shown. Serelaxin and zaprinast are both able to increase cGMP signalling via influencing two independent pharmacological targets. Serelaxin is currently in phase III development for acute heart failure and has shown Antifibrotic properties in several in vitro and in vivo experiments. It is discussed that serelaxin inhibits TGF-b signalling via RXFP1 receptor. Involvement of NO / cGMP in this process has also been revealed. Zaprinast is a selective inhibitor of phosphodiesterase V, which leads to enhanced levels of cGMP by blocking cGMP degradation.
Elisabeth Schinner - One of the best experts on this subject based on the ideXlab platform.
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Differences in the renal Antifibrotic cGMP/cGKI-dependent signaling of serelaxin, zaprinast, and their combination
Naunyn-Schmiedeberg's Archives of Pharmacology, 2017Co-Authors: Veronika Wetzl, Elisabeth Schinner, Lothar Faerber, Frieder Kees, Jens SchlossmannAbstract:Renal fibrosis is an important factor for end-stage renal failure. However, only few therapeutic options for its treatment are established. Zaprinast, a phosphodiesterase 5 inhibitor, and serelaxin, the recombinant form of the naturally occurring hormone relaxin, are differently acting modulators of cyclic guanosine monophosphate (cGMP) signaling. Both agents enhance cGMP availability in kidney tissue. These substances alone or in combination might interfere with the development of kidney fibrosis. Therefore, we compared the effects of combination therapy with the effects of monotherapy on renal fibrosis. Renal fibrosis was induced by unilateral ureteral obstruction (UUO) for 7 days in wild-type (WT) and cGKI knockout (KO) mice. Renal Antifibrotic effects were assessed after 7 days. In WT, zaprinast and the combination of zaprinast and serelaxin significantly reduced renal interstitial fibrosis assessed by α-SMA, fibronectin, collagen1A1, and gelatinases (MMP2 and MMP9). Intriguingly in cGKI-KO, mRNA and protein expression of fibronectin and collagen1A1 were reduced by zaprinast, in contrast to serelaxin. Gelatinases are not regulated by zaprinast. Although both substances showed similar Antifibrotic properties in WT, they distinguished in their effect mechanisms. In contrast to serelaxin which acts both on Smad2 and Erk1, zaprinast did not significantly diminish Erk1/2 phosphorylation. Interestingly, the combination of serelaxin/zaprinast achieved no additive Antifibrotic effects compared to the monotherapy. Due to Antifibrotic effects of zaprinast in cGKI-KO, we hypothesize that additional cGKI-independent mechanisms are supposed for Antifibrotic signaling of zaprinast.
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differences in the renal Antifibrotic cgmp cgki dependent signaling of serelaxin zaprinast and their combination
Naunyn-schmiedebergs Archives of Pharmacology, 2017Co-Authors: Veronika Wetzl, Elisabeth Schinner, Lothar Faerber, Frieder Kees, Jens SchlossmannAbstract:Renal fibrosis is an important factor for end-stage renal failure. However, only few therapeutic options for its treatment are established. Zaprinast, a phosphodiesterase 5 inhibitor, and serelaxin, the recombinant form of the naturally occurring hormone relaxin, are differently acting modulators of cyclic guanosine monophosphate (cGMP) signaling. Both agents enhance cGMP availability in kidney tissue. These substances alone or in combination might interfere with the development of kidney fibrosis. Therefore, we compared the effects of combination therapy with the effects of monotherapy on renal fibrosis. Renal fibrosis was induced by unilateral ureteral obstruction (UUO) for 7 days in wild-type (WT) and cGKI knockout (KO) mice. Renal Antifibrotic effects were assessed after 7 days. In WT, zaprinast and the combination of zaprinast and serelaxin significantly reduced renal interstitial fibrosis assessed by α-SMA, fibronectin, collagen1A1, and gelatinases (MMP2 and MMP9). Intriguingly in cGKI-KO, mRNA and protein expression of fibronectin and collagen1A1 were reduced by zaprinast, in contrast to serelaxin. Gelatinases are not regulated by zaprinast. Although both substances showed similar Antifibrotic properties in WT, they distinguished in their effect mechanisms. In contrast to serelaxin which acts both on Smad2 and Erk1, zaprinast did not significantly diminish Erk1/2 phosphorylation. Interestingly, the combination of serelaxin/zaprinast achieved no additive Antifibrotic effects compared to the monotherapy. Due to Antifibrotic effects of zaprinast in cGKI-KO, we hypothesize that additional cGKI-independent mechanisms are supposed for Antifibrotic signaling of zaprinast.
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involvement of cyclic guanosine monophosphate dependent protein kinase i in renal Antifibrotic effects of serelaxin
Frontiers in Pharmacology, 2016Co-Authors: Veronika Wetzl, Elisabeth Schinner, Lothar Faerber, Frieder Kees, Franz Hofmann, Jens SchlossmannAbstract: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 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 ureter 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 CTGF 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.
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Differences in the renal Antifibrotic signaling of serelaxin and zaprinast.
BMC Clinical Pharmacology, 2015Co-Authors: Veronika Wetzl, Elisabeth Schinner, Lothar Faerber, Franz Hofmann, Jens SchlossmannAbstract:Background Kidney fibrosis is frequently observed in cardiorenal diseases. Cyclic guanosine monophosphate (cGMP) serves as the most important second messenger of nitric oxide (NO) and has shown Antifibrotic effects at enhanced levels in several experimental models of kidney diseases. Antifibrotic effects of cGMP signalling via cGMP-dependent protein kinases (cGK), in particular cGKI, have already been shown. Serelaxin and zaprinast are both able to increase cGMP signalling via influencing two independent pharmacological targets. Serelaxin is currently in phase III development for acute heart failure and has shown Antifibrotic properties in several in vitro and in vivo experiments. It is discussed that serelaxin inhibits TGF-b signalling via RXFP1 receptor. Involvement of NO / cGMP in this process has also been revealed. Zaprinast is a selective inhibitor of phosphodiesterase V, which leads to enhanced levels of cGMP by blocking cGMP degradation.
Keizo Kanasaki - One of the best experts on this subject based on the ideXlab platform.
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Effect of Antifibrotic MicroRNAs Crosstalk on the Action of N-acetyl-seryl-aspartyl-lysyl-proline in Diabetes-related Kidney Fibrosis.
Scientific reports, 2016Co-Authors: Swayam Prakash Srivastava, Sen Shi, Megumi Kanasaki, Takako Nagai, Munehiro Kitada, Yuka Nakamura, Yasuhito Ishigaki, Keizo Kanasaki, Daisuke KoyaAbstract:N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is an endogenous Antifibrotic peptide. We found that suppression of AcSDKP and induction of dipeptidyl peptidase-4 (DPP-4), which is associated with insufficient levels of Antifibrotic microRNA (miR)s in kidneys, were imperative to understand the mechanisms of fibrosis in the diabetic kidneys. Analyzing streptozotocin (STZ)-induced diabetic mouse strains, diabetic CD-1 mice with fibrotic kidneys could be differentiated from less-fibrotic diabetic 129Sv mice by suppressing AcSDKP and Antifibrotic miRs (miR-29s and miR-let-7s), as well as by the prominent induction of DPP-4 protein expression/activity and endothelial to mesenchymal transition. In diabetic CD-1 mice, these alterations were all reversed by AcSDKP treatment. Transfection studies in culture endothelial cells demonstrated crosstalk regulation of miR-29s and miR-let-7s against mesenchymal activation program; such bidirectional regulation could play an essential role in maintaining the Antifibrotic program of AcSDKP. Finally, we observed that AcSDKP suppression in fibrotic mice was associated with induction of both interferon-γ and transforming growth factor-β signaling, crucial molecular pathways that disrupt Antifibrotic miRs crosstalk. The present study provides insight into the physiologically relevant Antifibrotic actions of AcSDKP via Antifibrotic miRs; restoring such Antifibrotic programs could demonstrate potential utility in combating kidney fibrosis in diabetes.
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Elevation of the Antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline: a blood pressure-independent beneficial effect of angiotensin I-converting enzyme inhibitors.
Fibrogenesis & tissue repair, 2011Co-Authors: Megumi Kanasaki, Takako Nagai, Munehiro Kitada, Daisuke Koya, Keizo KanasakiAbstract:Blockade of the renin-angiotensin system (RAS) is well recognized as an essential therapy in hypertensive, heart, and kidney diseases. There are several classes of drugs that block the RAS; these drugs are known to exhibit Antifibrotic action. An analysis of the molecular mechanisms of action for these drugs can reveal potential differences in their Antifibrotic roles. In this review, we discuss the Antifibrotic action of RAS blockade with an emphasis on the potential importance of angiotensin I-converting enzyme (ACE) inhibition associated with the Antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP).