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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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fibrose assoziierte biomarker einfluss der behandlung mit serelaxin im murinen nierenfibrose modell und pradiktiver aussagewert in der pulmonalen hypertonie
2017Co-Authors: Veronika WetzlAbstract:Die Fibrose stellt aufgrund ihrer hohen Pravalenz in der Bevolkerung, der schlechten Prognose fur die Patienten, sowie der komplexen Pathophysiologie ein sehr wichtiges Forschungsgebiet mit einem hohen Bedarf an neuen Therapeutika dar. Serelaxin zeigte in diversen Indikationen bereits eine organprotektive Wirkung, welche unter anderem auf die antifibrotischen Eigenschaften der Substanz zuruckzufuhren sind. Hier konnte der second messenger cGMP und die abhangige Proteinkinase cGKI eine entscheidende Rolle spielen. Auch in der Therapie der pulmonalen Hypertonie sind cGMP-modulierende Pharmaka, wie z. B. Inhibitoren der Phosphodiesterase 5 oder Stimulatoren der loslichen Guanylatzyklase, im Einsatz. Aufgrund der schlechten Prognose ist hier der Bedarf an weiteren innovativen Pharmaka als auch neuen prognostischen Markern – beispielsweise Fibrose-assoziierten Biomarkern – hoch. Ziel der Arbeit war es, einerseits Erkenntnisse uber cGKI – eine cGMP-abhangige Proteinkinase – und deren Substrate in der renalen Fibrose unter Einfluss von Serelaxin zu gewinnen. Dies wurde in Wildtyp- sowie cGKI-KO Mausen mithilfe der unilateralen Ureterligation untersucht, welche ein etabliertes Modell fur die tubulointerstitielle Nierenfibrose darstellt. Zusatzlich wurde getestet, ob durch die Gabe des PDE5-Inhibitors Zaprinast ahnliche bzw. additive antifibrotische Effekte in der Niere erzielt wurden. In einer weiteren Untersuchung wurde anschliesend an Patienten mit pulmonaler Hypertonie die klinische Relevanz ausgewahlter Fibrose-assoziierter Biomarker – der MMP/TIMP-Verhaltnisse – evaluiert, indem ein biologischer Marker identifiziert wurde, der mit dem Krankheitsverlauf sowie der Prognose assoziiert ist und zugleich mit den antifibrotischen Effekten von Serelaxin verknupft ist. Im renalen Nierenfibrose-Modell waren die cGMP-Konzentrationen im fibrotischen Nierengewebe nach 7-tagiger Behandlung mit Serelaxin, Zaprinast sowie der Kombination beider Pharmaka erhoht. In WT Mausen konnten ahnliche uber die NO-cGMP-abhangige Proteinkinase cGKI vermittelte antifibrotische Effekte in allen drei Behandlungsgruppen beobachtet werden. Die Verabreichung von Serelaxin fuhrte hierbei vermutlich uber die Hemmung der Smad2- und ERK1-Phosphorylierung zu einer Reduzierung von Bestandteilen der extrazellularen Matrix (z. B. Kollagene, Fibronektin). Die 7-tagige Behandlung mit dem Phosphodiesterase-5-Hemmer Zaprinast resultierte in einer tendenziell verringerten ERK1- und ERK2-Phosphorylierung ohne Einfluss auf die Smad2-Phosphorylierung. Zusatzlich wurde mit Zaprinast die antifibrotische Wirkung uber cGKI-unabhangige Mechanismen vermittelt. Die Kombination der beiden cGMP-erhohenden Therapieoptionen war nicht antifibrotisch wirksamer als die jeweiligen Einzelsubstanzen. Matrix-Metalloproteinasen – Proteine, die fur den Umbau der extrazellularen Matrix verantwortlich sind – wurden nur durch die 7-tagige Serelaxin-Behandlung positiv moduliert, indem das in der Fibrose stark erhohte Angebot an MMP2 reduziert wurde. Die in der Fibrose nahezu unveranderte MMP9-Proteinexpression wurde nach Serelaxin-Gabe lediglich vermehrt in die aktive Form uberfuhrt. Weiterhin wurde in Patienten mit pulmonaler Hypertonie die klinische Relevanz von Matrix-Metalloproteinasen (MMP2, MMP9) und deren Inhibitoren (TIMP1, TIMP4) untersucht. Dazu wurde in einem Patientenkollektiv mit idiopathischer pulmonalarterieller Hypertonie (n=24) sowie pulmonaler Hypertonie aufgrund einer Linksherzinsuffizienz (n=11) nachgewiesen, dass durch den Fibrose-assoziierten Biomarker MMP2/TIMP4 ein Zusammenhang mit der Hamodynamik (mPAP, PVR) sowie der rechtsventrikularen Funktion (TAPSE) gezeigt werden konnte. Zusatzlich war MMP2/TIMP4 in Patienten mit iPAH pradiktiv fur das klinische Outcome (klinische Verschlechterung, Tod). Die Ergebnisse dieser Arbeit haben also gezeigt, dass Serelaxin in der Nierenfibrose uber die NO-cGMP-cGKI-Signalkaskade antifibrotisch wirkt, unter anderem durch die Modulation der Matrix-Metalloproteinasen. Zusatzlich haben sich Matrix-Metalloproteinasen und deren Inhibitoren bei Patienten mit pulmonaler Hypertonie, einer kardiovaskularen Erkrankung charakterisiert durch fibrotischen Gewebeumbau, als prognostisch wertvoll erwiesen.
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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.
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.
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.
Frieder Kees - 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.
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.
