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Olena Andrukhova - One of the best experts on this subject based on the ideXlab platform.
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Development of Heart Hypertrophy and pro-inflammatory response post-MI do not differ between VDR-ablated mice and WT mice on rescue diet.
2018Co-Authors: Kristopher Ford, Svetlana Slavic, Ute Zeitz, Reinhold G Erben, Nejla Latic, Marlies Dolezal, Oleh Andrukhov, Olena AndrukhovaAbstract:Example of histological sections from the left ventricle, stained with wheat germ agglutinin (WGA) and accompanying quantification of cardiomyocyte area (A), Heart/body weight (HW/BW) ratio (B), left ventricle αSMA (α-smooth muscle actin), ANP (atrial natriuretic peptide) and BNP (B-type natriuretic peptide) mRNA expression (C), serum IL-1β and TNF-α levels (D), and mRNA expression of IL-1β and TNF-α from the left ventricle and from the right ventricle and septum (E+F) of WT and VDR mutants at 8 weeks (8W) post sham (S) or MI (M) surgery. Groups sizes for A, n = 4–6 and for B and C, n = 5–7. Individual values are given in S1 Data. * p < 0.05; ** p < 0.01 versus sham of corresponding genotype by least square means (LSM) linear model with Bonferroni post hoc correction for multiple testing. not detectable (ND).
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genetic ablation of fgf23 or klotho does not modulate experimental Heart Hypertrophy induced by pressure overload
Scientific Reports, 2017Co-Authors: Svetlana Slavic, Ute Zeitz, Reinhold G Erben, Kristopher Ford, Magalie Modert, Amarela Becirovic, Stephan Handschuh, Andreas Baierl, Nejla Katica, Olena AndrukhovaAbstract:Left ventricular Hypertrophy (LVH) ultimately leads to Heart failure in conditions of increased cardiac pre- or afterload. The bone-derived phosphaturic and sodium-conserving hormone fibroblast growth factor-23 (FGF23) and its co-receptor Klotho have been implicated in the development of uremic LVH. Using transverse aortic constriction (TAC) in gene-targeted mouse models, we examine the role of Fgf23 and Klotho in cardiac Hypertrophy and dysfunction induced by pressure overload. TAC profoundly increases serum intact Fgf23 due to increased cardiac and bony Fgf23 transcription and downregulation of Fgf23 cleavage. Aldosterone receptor blocker spironolactone normalizes serum intact Fgf23 levels after TAC by reducing bony Fgf23 transcription. Notably, genetic Fgf23 or Klotho deficiency does not influence TAC-induced hypertrophic remodelling, LV functional impairment, or LV fibrosis. Despite the profound, aldosterone-mediated increase in circulating intact Fgf23 after TAC, our data do not support an essential role of Fgf23 or Klotho in the pathophysiology of pressure overload-induced cardiac Hypertrophy.
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Research Article FGF23 regulates renal sodium handling and blood pressure
2016Co-Authors: Olena Andrukhova, Svetlana Slavic, Alina Smorodchenko, Ute Zeitz, Victoria Shalhoub, Elena E Pohl, Reinhold G ErbenAbstract:Fibroblast growth factor-23 (FGF23) is a bone-derived hormone regulating renal phosphate reabsorption and vitamin D synthesis in renal proximal tubules. Here, we show that FGF23 directly regu-lates the membrane abundance of the Na+:Cl co-transporter NCC in distal renal tubules by a signaling mechanism involving the FGF receptor/aKlotho complex, extracellular signal-regulated kinase 1/2 (ERK1/2), serum/glucocorticoid-regulated kinase 1 (SGK1), and with-no lysine kinase-4 (WNK4). Renal sodium (Na+) reabsorption and distal tubular membrane expression of NCC are reduced in mouse models of Fgf23 and aKlotho deficiency. Conversely, gain of FGF23 function by injection of wild-type mice with recombinant FGF23 or by elevated circulating levels of endogenous Fgf23 in Hyp mice increases distal tubular Na+ uptake and membrane abun-dance of NCC, leading to volume expansion, hypertension, and Heart Hypertrophy in a aKlotho and dietary Na+-dependent fashion. The NCC inhibitor chlorothiazide abrogates FGF23-induced volume expansion and Heart Hypertrophy. Our findings suggest that FGF23 is a key regulator of renal Na+ reabsorption and plasma volume, and may explain the association of FGF23 with cardiovascular risk in chronic kidney disease patients
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Research Article FGF23 regulates renal sodium handling and blood pressure
2014Co-Authors: Olena Andrukhova, Svetlana Slavic, Alina Smorodchenko, Ute Zeitz, Victoria Shalhoub, Elena E Pohl, Reinhold G ErbenAbstract:Fibroblast growth factor-23 (FGF23) is a bone-derived hormone regulating renal phosphate reabsorption and vitamin D synthesis in renal proximal tubules. Here, we show that FGF23 directly regu-lates the membrane abundance of the Na+:Cl co-transporter NCC in distal renal tubules by a signaling mechanism involving the FGF receptor/aKlotho complex, extracellular signal-regulated kinase 1/2 (ERK1/2), serum/glucocorticoid-regulated kinase 1 (SGK1), and with-no lysine kinase-4 (WNK4). Renal sodium (Na+) reabsorption and distal tubular membrane expression of NCC are reduced in mouse models of Fgf23 and aKlotho deficiency. Conversely, gain of FGF23 function by injection of wild-type mice with recombinant FGF23 or by elevated circulating levels of endogenous Fgf23 in Hyp mice increases distal tubular Na+ uptake and membrane abun-dance of NCC, leading to volume expansion, hypertension, and Heart Hypertrophy in a aKlotho and dietary Na+-dependent fashion. The NCC inhibitor chlorothiazide abrogates FGF23-induced volume expansion and Heart Hypertrophy. Our findings suggest that FGF23 is a key regulator of renal Na+ reabsorption and plasma volume, and may explain the association of FGF23 with cardiovascular risk in chronic kidney disease patients. Keywords aldosterone; blood pressure; fibroblast growth factor-23; Heart Hypertrophy; sodium homeostasi
Norbert Weissmann - One of the best experts on this subject based on the ideXlab platform.
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The role of mitochondrial reactive oxygen species in the response of the pulmonary vasculature to hypoxia and right Heart remodeling
Free Radical Biology and Medicine, 2017Co-Authors: Susan Scheibe, Azadeh Esfandiary, Akylbek Sydykov, Norbert Weissmann, Michael P Murphy, Natascha SommerAbstract:Introduction Increased release of mitochondrial superoxide has been suggested to mediate acute hypoxic pulmonary vasoconstriction (HPV) as well as chronic hypoxia-induced pulmonary hypertension (PH) and right Heart remodeling. Thus, we investigated the superoxide release during HPV, chronic hypoxia-induced PH and after pulmonary arterial banding (PAB), as well as the effect of the mitochondria-targeted antioxidant MitoQ on these processes. Results Superoxide levels were increased in PASMC during acute hypoxia, and decreased after 5 days of hypoxia. In parallel MitoQ, but not its inactive carrier substance, TPP+, significantly inhibited acute HPV and the rise in superoxide concentration induced by acute hypoxia. However, MitoQ application did not affect the hypoxia-induced proliferation of PASMC or the development of chronic hypoxia-induced PH. In contrast, MitoQ application attenuated right ventricular remodeling after chronic hypoxic exposure as well as after PAB with regard to development of right Heart Hypertrophy and dilatation. Accordingly, superoxide levels were increased in the RV after PAB. Conclusion Increased superoxide concentration mediates acute HPV, while decreased superoxide levels were detected in chronic hypoxia-induced PH. MitoQ may be beneficial under conditions of exaggerated acute HPV and to prevent the development of right Heart remodeling.
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pro proliferative and inflammatory signaling converge on foxo1 transcription factor in pulmonary hypertension
Nature Medicine, 2014Co-Authors: Rajkumar Savai, Norbert Weissmann, Hamza M Altamari, Daniel Sedding, Baktybek Kojonazarov, Christian Muecke, Rebecca Teske, Mario R Capecchi, Friedrich Grimminger, Werner SeegerAbstract:Pulmonary hypertension (PH) is characterized by increased proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs). Forkhead box O (FoxO) transcription factors are key regulators of cellular proliferation. Here we show that in pulmonary vessels and PASMCs of human and experimental PH lungs, FoxO1 expression is downregulated and FoxO1 is inactivated via phosphorylation and nuclear exclusion. These findings could be reproduced using ex vivo exposure of PASMCs to growth factors and inflammatory cytokines. Pharmacological inhibition and genetic ablation of FoxO1 in smooth muscle cells reproduced PH features in vitro and in vivo. Either pharmacological reconstitution of FoxO1 activity using intravenous or inhaled paclitaxel, or reconstitution of the transcriptional activity of FoxO1 by gene therapy, restored the physiologically quiescent PASMC phenotype in vitro, linked to changes in cell cycle control and bone morphogenic protein receptor type 2 (BMPR2) signaling, and reversed vascular remodeling and right-Heart Hypertrophy in vivo. Thus, PASMC FoxO1 is a critical integrator of multiple signaling pathways driving PH, and reconstitution of FoxO1 activity offers a potential therapeutic option for PH.
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the soluble guanylate cyclase activator hmr1766 reverses hypoxia induced experimental pulmonary hypertension in mice
American Journal of Physiology-lung Cellular and Molecular Physiology, 2009Co-Authors: Norbert Weissmann, Beate Fuchs, S Hackemack, Bhola K Dahal, Soni Savai Pullamsetti, Rajkumar Savai, Manish Mittal, Thomas Medebach, Rio Dumitrascu, Martin Van EickelsAbstract:Severe pulmonary hypertension (PH) is a disabling disease with high mortality, characterized by pulmonary vascular remodeling and right Heart Hypertrophy. In mice with PH induced by chronic hypoxia...
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activation of soluble guanylate cyclase reverses experimental pulmonary hypertension and vascular remodeling
Circulation, 2006Co-Authors: Rio Dumitrascu, Norbert Weissmann, Johannespeter Stasch, Werner Seeger, Hossein Ardeschir Ghofrani, Eva Dony, Knut Beuerlein, Harald H H W Schmidt, Mark Jean Gnoth, Friedrich GrimmingerAbstract:Background— Severe pulmonary hypertension is a disabling disease with high mortality, characterized by pulmonary vascular remodeling and right Heart Hypertrophy. Using wild-type and homozygous endothelial nitric oxide synthase (NOS3−/−) knockout mice with pulmonary hypertension induced by chronic hypoxia and rats with monocrotaline-induced pulmonary hypertension, we examined whether the soluble guanylate cyclase (sGC) stimulator Bay41-2272 or the sGC activator Bay58-2667 could reverse pulmonary vascular remodeling. Methods and Results— Both Bay41-2272 and Bay58-2667 dose-dependently inhibited the pressor response of acute hypoxia in the isolated perfused lung system. When wild-type (NOS3+/+) or NOS3−/− mice were housed under 10% oxygen conditions for 21 or 35 days, both strains developed pulmonary hypertension, right Heart Hypertrophy, and pulmonary vascular remodeling, demonstrated by an increase in fully muscularized peripheral pulmonary arteries. Treatment of wild-type mice with the activator of sGC, B...
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reversal of experimental pulmonary hypertension by pdgf inhibition
Journal of Clinical Investigation, 2005Co-Authors: Ralph T. Schermuly, Akylbek Sydykov, Norbert Weissmann, Soni Savai Pullamsetti, Rajkumar Savai, Hossein Ardeschir Ghofrani, Eva Dony, Markus Roth, Ying Ju Lai, Werner SeegerAbstract:Progression of pulmonary hypertension is associated with increased proliferation and migration of pulmonary vascular smooth muscle cells. PDGF is a potent mitogen and involved in this process. We now report that the PDGF receptor antagonist STI571 (imatinib) reversed advanced pulmonary vascular disease in 2 animal models of pulmonary hypertension. In rats with monocrotaline-induced pulmonary hypertension, therapy with daily administration of STI571 was started 28 days after induction of the disease. A 2-week treatment resulted in 100% survival, compared with only 50% in sham-treated rats. The changes in RV pressure, measured continuously by telemetry, and right Heart Hypertrophy were reversed to near-normal levels. STI571 prevented phosphorylation of the PDGF receptor and suppressed activation of downstream signaling pathways. Similar results were obtained in chronically hypoxic mice, which were treated with STI571 after full establishment of pulmonary hypertension. Moreover, expression of the PDGF receptor was found to be significantly increased in lung tissue from pulmonary arterial hypertension patients compared with healthy donor lung tissue. We conclude that STI571 reverses vascular remodeling and cor pulmonale in severe experimental pulmonary hypertension regardless of the initiating stimulus. This regimen offers a unique novel approach for antire-modeling therapy in progressed pulmonary hypertension.
Reinhold G Erben - One of the best experts on this subject based on the ideXlab platform.
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Development of Heart Hypertrophy and pro-inflammatory response post-MI do not differ between VDR-ablated mice and WT mice on rescue diet.
2018Co-Authors: Kristopher Ford, Svetlana Slavic, Ute Zeitz, Reinhold G Erben, Nejla Latic, Marlies Dolezal, Oleh Andrukhov, Olena AndrukhovaAbstract:Example of histological sections from the left ventricle, stained with wheat germ agglutinin (WGA) and accompanying quantification of cardiomyocyte area (A), Heart/body weight (HW/BW) ratio (B), left ventricle αSMA (α-smooth muscle actin), ANP (atrial natriuretic peptide) and BNP (B-type natriuretic peptide) mRNA expression (C), serum IL-1β and TNF-α levels (D), and mRNA expression of IL-1β and TNF-α from the left ventricle and from the right ventricle and septum (E+F) of WT and VDR mutants at 8 weeks (8W) post sham (S) or MI (M) surgery. Groups sizes for A, n = 4–6 and for B and C, n = 5–7. Individual values are given in S1 Data. * p < 0.05; ** p < 0.01 versus sham of corresponding genotype by least square means (LSM) linear model with Bonferroni post hoc correction for multiple testing. not detectable (ND).
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genetic ablation of fgf23 or klotho does not modulate experimental Heart Hypertrophy induced by pressure overload
Scientific Reports, 2017Co-Authors: Svetlana Slavic, Ute Zeitz, Reinhold G Erben, Kristopher Ford, Magalie Modert, Amarela Becirovic, Stephan Handschuh, Andreas Baierl, Nejla Katica, Olena AndrukhovaAbstract:Left ventricular Hypertrophy (LVH) ultimately leads to Heart failure in conditions of increased cardiac pre- or afterload. The bone-derived phosphaturic and sodium-conserving hormone fibroblast growth factor-23 (FGF23) and its co-receptor Klotho have been implicated in the development of uremic LVH. Using transverse aortic constriction (TAC) in gene-targeted mouse models, we examine the role of Fgf23 and Klotho in cardiac Hypertrophy and dysfunction induced by pressure overload. TAC profoundly increases serum intact Fgf23 due to increased cardiac and bony Fgf23 transcription and downregulation of Fgf23 cleavage. Aldosterone receptor blocker spironolactone normalizes serum intact Fgf23 levels after TAC by reducing bony Fgf23 transcription. Notably, genetic Fgf23 or Klotho deficiency does not influence TAC-induced hypertrophic remodelling, LV functional impairment, or LV fibrosis. Despite the profound, aldosterone-mediated increase in circulating intact Fgf23 after TAC, our data do not support an essential role of Fgf23 or Klotho in the pathophysiology of pressure overload-induced cardiac Hypertrophy.
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Research Article FGF23 regulates renal sodium handling and blood pressure
2016Co-Authors: Olena Andrukhova, Svetlana Slavic, Alina Smorodchenko, Ute Zeitz, Victoria Shalhoub, Elena E Pohl, Reinhold G ErbenAbstract:Fibroblast growth factor-23 (FGF23) is a bone-derived hormone regulating renal phosphate reabsorption and vitamin D synthesis in renal proximal tubules. Here, we show that FGF23 directly regu-lates the membrane abundance of the Na+:Cl co-transporter NCC in distal renal tubules by a signaling mechanism involving the FGF receptor/aKlotho complex, extracellular signal-regulated kinase 1/2 (ERK1/2), serum/glucocorticoid-regulated kinase 1 (SGK1), and with-no lysine kinase-4 (WNK4). Renal sodium (Na+) reabsorption and distal tubular membrane expression of NCC are reduced in mouse models of Fgf23 and aKlotho deficiency. Conversely, gain of FGF23 function by injection of wild-type mice with recombinant FGF23 or by elevated circulating levels of endogenous Fgf23 in Hyp mice increases distal tubular Na+ uptake and membrane abun-dance of NCC, leading to volume expansion, hypertension, and Heart Hypertrophy in a aKlotho and dietary Na+-dependent fashion. The NCC inhibitor chlorothiazide abrogates FGF23-induced volume expansion and Heart Hypertrophy. Our findings suggest that FGF23 is a key regulator of renal Na+ reabsorption and plasma volume, and may explain the association of FGF23 with cardiovascular risk in chronic kidney disease patients
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Research Article FGF23 regulates renal sodium handling and blood pressure
2014Co-Authors: Olena Andrukhova, Svetlana Slavic, Alina Smorodchenko, Ute Zeitz, Victoria Shalhoub, Elena E Pohl, Reinhold G ErbenAbstract:Fibroblast growth factor-23 (FGF23) is a bone-derived hormone regulating renal phosphate reabsorption and vitamin D synthesis in renal proximal tubules. Here, we show that FGF23 directly regu-lates the membrane abundance of the Na+:Cl co-transporter NCC in distal renal tubules by a signaling mechanism involving the FGF receptor/aKlotho complex, extracellular signal-regulated kinase 1/2 (ERK1/2), serum/glucocorticoid-regulated kinase 1 (SGK1), and with-no lysine kinase-4 (WNK4). Renal sodium (Na+) reabsorption and distal tubular membrane expression of NCC are reduced in mouse models of Fgf23 and aKlotho deficiency. Conversely, gain of FGF23 function by injection of wild-type mice with recombinant FGF23 or by elevated circulating levels of endogenous Fgf23 in Hyp mice increases distal tubular Na+ uptake and membrane abun-dance of NCC, leading to volume expansion, hypertension, and Heart Hypertrophy in a aKlotho and dietary Na+-dependent fashion. The NCC inhibitor chlorothiazide abrogates FGF23-induced volume expansion and Heart Hypertrophy. Our findings suggest that FGF23 is a key regulator of renal Na+ reabsorption and plasma volume, and may explain the association of FGF23 with cardiovascular risk in chronic kidney disease patients. Keywords aldosterone; blood pressure; fibroblast growth factor-23; Heart Hypertrophy; sodium homeostasi
Svetlana Slavic - One of the best experts on this subject based on the ideXlab platform.
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Development of Heart Hypertrophy and pro-inflammatory response post-MI do not differ between VDR-ablated mice and WT mice on rescue diet.
2018Co-Authors: Kristopher Ford, Svetlana Slavic, Ute Zeitz, Reinhold G Erben, Nejla Latic, Marlies Dolezal, Oleh Andrukhov, Olena AndrukhovaAbstract:Example of histological sections from the left ventricle, stained with wheat germ agglutinin (WGA) and accompanying quantification of cardiomyocyte area (A), Heart/body weight (HW/BW) ratio (B), left ventricle αSMA (α-smooth muscle actin), ANP (atrial natriuretic peptide) and BNP (B-type natriuretic peptide) mRNA expression (C), serum IL-1β and TNF-α levels (D), and mRNA expression of IL-1β and TNF-α from the left ventricle and from the right ventricle and septum (E+F) of WT and VDR mutants at 8 weeks (8W) post sham (S) or MI (M) surgery. Groups sizes for A, n = 4–6 and for B and C, n = 5–7. Individual values are given in S1 Data. * p < 0.05; ** p < 0.01 versus sham of corresponding genotype by least square means (LSM) linear model with Bonferroni post hoc correction for multiple testing. not detectable (ND).
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genetic ablation of fgf23 or klotho does not modulate experimental Heart Hypertrophy induced by pressure overload
Scientific Reports, 2017Co-Authors: Svetlana Slavic, Ute Zeitz, Reinhold G Erben, Kristopher Ford, Magalie Modert, Amarela Becirovic, Stephan Handschuh, Andreas Baierl, Nejla Katica, Olena AndrukhovaAbstract:Left ventricular Hypertrophy (LVH) ultimately leads to Heart failure in conditions of increased cardiac pre- or afterload. The bone-derived phosphaturic and sodium-conserving hormone fibroblast growth factor-23 (FGF23) and its co-receptor Klotho have been implicated in the development of uremic LVH. Using transverse aortic constriction (TAC) in gene-targeted mouse models, we examine the role of Fgf23 and Klotho in cardiac Hypertrophy and dysfunction induced by pressure overload. TAC profoundly increases serum intact Fgf23 due to increased cardiac and bony Fgf23 transcription and downregulation of Fgf23 cleavage. Aldosterone receptor blocker spironolactone normalizes serum intact Fgf23 levels after TAC by reducing bony Fgf23 transcription. Notably, genetic Fgf23 or Klotho deficiency does not influence TAC-induced hypertrophic remodelling, LV functional impairment, or LV fibrosis. Despite the profound, aldosterone-mediated increase in circulating intact Fgf23 after TAC, our data do not support an essential role of Fgf23 or Klotho in the pathophysiology of pressure overload-induced cardiac Hypertrophy.
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Research Article FGF23 regulates renal sodium handling and blood pressure
2016Co-Authors: Olena Andrukhova, Svetlana Slavic, Alina Smorodchenko, Ute Zeitz, Victoria Shalhoub, Elena E Pohl, Reinhold G ErbenAbstract:Fibroblast growth factor-23 (FGF23) is a bone-derived hormone regulating renal phosphate reabsorption and vitamin D synthesis in renal proximal tubules. Here, we show that FGF23 directly regu-lates the membrane abundance of the Na+:Cl co-transporter NCC in distal renal tubules by a signaling mechanism involving the FGF receptor/aKlotho complex, extracellular signal-regulated kinase 1/2 (ERK1/2), serum/glucocorticoid-regulated kinase 1 (SGK1), and with-no lysine kinase-4 (WNK4). Renal sodium (Na+) reabsorption and distal tubular membrane expression of NCC are reduced in mouse models of Fgf23 and aKlotho deficiency. Conversely, gain of FGF23 function by injection of wild-type mice with recombinant FGF23 or by elevated circulating levels of endogenous Fgf23 in Hyp mice increases distal tubular Na+ uptake and membrane abun-dance of NCC, leading to volume expansion, hypertension, and Heart Hypertrophy in a aKlotho and dietary Na+-dependent fashion. The NCC inhibitor chlorothiazide abrogates FGF23-induced volume expansion and Heart Hypertrophy. Our findings suggest that FGF23 is a key regulator of renal Na+ reabsorption and plasma volume, and may explain the association of FGF23 with cardiovascular risk in chronic kidney disease patients
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Research Article FGF23 regulates renal sodium handling and blood pressure
2014Co-Authors: Olena Andrukhova, Svetlana Slavic, Alina Smorodchenko, Ute Zeitz, Victoria Shalhoub, Elena E Pohl, Reinhold G ErbenAbstract:Fibroblast growth factor-23 (FGF23) is a bone-derived hormone regulating renal phosphate reabsorption and vitamin D synthesis in renal proximal tubules. Here, we show that FGF23 directly regu-lates the membrane abundance of the Na+:Cl co-transporter NCC in distal renal tubules by a signaling mechanism involving the FGF receptor/aKlotho complex, extracellular signal-regulated kinase 1/2 (ERK1/2), serum/glucocorticoid-regulated kinase 1 (SGK1), and with-no lysine kinase-4 (WNK4). Renal sodium (Na+) reabsorption and distal tubular membrane expression of NCC are reduced in mouse models of Fgf23 and aKlotho deficiency. Conversely, gain of FGF23 function by injection of wild-type mice with recombinant FGF23 or by elevated circulating levels of endogenous Fgf23 in Hyp mice increases distal tubular Na+ uptake and membrane abun-dance of NCC, leading to volume expansion, hypertension, and Heart Hypertrophy in a aKlotho and dietary Na+-dependent fashion. The NCC inhibitor chlorothiazide abrogates FGF23-induced volume expansion and Heart Hypertrophy. Our findings suggest that FGF23 is a key regulator of renal Na+ reabsorption and plasma volume, and may explain the association of FGF23 with cardiovascular risk in chronic kidney disease patients. Keywords aldosterone; blood pressure; fibroblast growth factor-23; Heart Hypertrophy; sodium homeostasi
Ralph T. Schermuly - One of the best experts on this subject based on the ideXlab platform.
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expression and function of soluble guanylate cyclase in pulmonary arterial hypertension
European Respiratory Journal, 2008Co-Authors: Ralph T. Schermuly, S Hackemack, Soni Savai Pullamsetti, Johannespeter Stasch, Ralf Middendorff, Dieter Muller, Klausdieter Schluter, A Dingendorf, Ewa Kolosionek, Christina KaulenAbstract:Alterations of the nitric oxide receptor, soluble guanylate cyclase (sGC) may contribute to the pathophysiology of pulmonary arterial hypertension (PAH). In the present study, the expression of sGC in explanted lung tissue of PAH patients was studied and the effects of the sGC stimulator BAY 63-2521 on enzyme activity, and haemodynamics and vascular remodelling were investigated in two independent animal models of PAH. Strong upregulation of sGC in pulmonary arterial vessels in the idiopathic PAH lungs compared with healthy donor lungs was demonstrated by immunohistochemistry. Upregulation of sGC was detected, similarly to humans, in the structurally remodelled smooth muscle layer in chronic hypoxic mouse lungs and lungs from monocrotaline (MCT)-injected rats. BAY 63-2521 is a novel, orally available compound that directly stimulates sGC and sensitises it to its physiological stimulator, nitric oxide. Chronic treatment of hypoxic mice and MCT-injected rats, with fully established PAH, with BAY 63-2521 (10 mg·kg−1·day−1) partially reversed the PAH, the right Heart Hypertrophy and the structural remodelling of the lung vasculature. Upregulation of soluble guanylate cyclase in pulmonary arterial smooth muscle cells was noted in human idiopathic pulmonary arterial hypertension lungs and lungs from animal models of pulmonary arterial hypertension. Stimulation of soluble guanylate cyclase reversed right Heart Hypertrophy and structural lung vascular remodelling. Soluble guanylate cyclase may thus offer a new target for therapeutic intervention in pulmonary arterial hypertension.
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reversal of experimental pulmonary hypertension by pdgf inhibition
Journal of Clinical Investigation, 2005Co-Authors: Ralph T. Schermuly, Akylbek Sydykov, Norbert Weissmann, Soni Savai Pullamsetti, Rajkumar Savai, Hossein Ardeschir Ghofrani, Eva Dony, Markus Roth, Ying Ju Lai, Werner SeegerAbstract:Progression of pulmonary hypertension is associated with increased proliferation and migration of pulmonary vascular smooth muscle cells. PDGF is a potent mitogen and involved in this process. We now report that the PDGF receptor antagonist STI571 (imatinib) reversed advanced pulmonary vascular disease in 2 animal models of pulmonary hypertension. In rats with monocrotaline-induced pulmonary hypertension, therapy with daily administration of STI571 was started 28 days after induction of the disease. A 2-week treatment resulted in 100% survival, compared with only 50% in sham-treated rats. The changes in RV pressure, measured continuously by telemetry, and right Heart Hypertrophy were reversed to near-normal levels. STI571 prevented phosphorylation of the PDGF receptor and suppressed activation of downstream signaling pathways. Similar results were obtained in chronically hypoxic mice, which were treated with STI571 after full establishment of pulmonary hypertension. Moreover, expression of the PDGF receptor was found to be significantly increased in lung tissue from pulmonary arterial hypertension patients compared with healthy donor lung tissue. We conclude that STI571 reverses vascular remodeling and cor pulmonale in severe experimental pulmonary hypertension regardless of the initiating stimulus. This regimen offers a unique novel approach for antire-modeling therapy in progressed pulmonary hypertension.
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antiremodeling effects of iloprost and the dual selective phosphodiesterase 3 4 inhibitor tolafentrine in chronic experimental pulmonary hypertension
Circulation Research, 2004Co-Authors: Ralph T. Schermuly, Norbert Weissmann, Soni Savai Pullamsetti, Werner Seeger, Christian Schudt, Hossein Ardeschir Ghofrani, Klaus Peter Kreisselmeier, Arun Samidurai, Leander Ermert, Friedrich GrimmingerAbstract:Severe pulmonary hypertension is a disabling disease with high mortality. We investigated acute and chronic effects of iloprost, a long-acting prostacyclin analogue, and the dual-selective phosphodiesterase 3/4 inhibitor tolafentrine in monocrotaline-induced pulmonary hypertension in rats. Twenty-eight and 42 days after administration of the alkaloid, right ventricular systolic pressure increased from 25.8+/-2.0 to 62.9+/-3.4 and 70.5+/-7.4 mm Hg, with concomitant decline in cardiac index, central venous oxygen saturation, and arterial oxygenation. Marked right Heart Hypertrophy was demonstrated by the strongly elevated ratio of right ventricle/left ventricle plus septum weight, and massive thickening of the precapillary artery smooth muscle layer was shown histologically. Western blot analysis demonstrated increased levels of matrix metalloproteinases (MMPs) -2 and -9 and increased gelatinolytic activities in isolated pulmonary arteries. In these animals, both intravenous iloprost and tolafentrine displayed characteristic features of pulmonary vasodilators. When chronically infused from days 14 to 28, both agents significantly attenuated all monocrotaline-induced hemodynamic and gas exchange abnormalities as well as right Heart Hypertrophy. Full normalization of all variables including right ventricle size was achieved on combined administration of both agents during this period. This was also true for MMP-2 and MMP-9 expression and activity. Moreover, when iloprost plus tolafentrine was used for late therapeutic intervention, with infusion from days 28 to 42 after full establishment of severe pulmonary hypertension and cor pulmonale, hemodynamic, gas exchange, and cardiac and pulmonary vascular remodeling changes were significantly reversed. We conclude that the combined administration of iloprost and a dual-selective phosphodiesterase 3/4 inhibitor prevents and reverses the development of pulmonary hypertension and cor pulmonale in response to monocrotaline in rats. This regimen may therefore offer a possible antiremodeling therapy in severe pulmonary hypertension.
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chronic sildenafil treatment inhibits monocrotaline induced pulmonary hypertension in rats
American Journal of Respiratory and Critical Care Medicine, 2004Co-Authors: Ralph T. Schermuly, Norbert Weissmann, Hossein Ardeschir Ghofrani, Klaus Peter Kreisselmeier, Leander Ermert, Huseyin Yilmaz, Ghazwan Butrous, Monika Ermert, Frank Rose, Andreas GuentherAbstract:Sildenafil, a phosphodiesterase 5 inhibitor, is currently under investigation for therapy of pulmonary hypertension. This study was designed to investigate chronic effects of sildenafil in monocrotaline (MCT)-induced pulmonary hypertension in rats. Four weeks after a single subcutaneous injection of MCT, the animals displayed nearly threefold elevated pulmonary artery pressure and vascular resistance values, with a concomitant decline in central venous oxygen saturation and arterial oxygenation. Marked right Heart Hypertrophy was evident, and massive thickening of the precapillary artery smooth muscle layer was histologically apparent. Further deterioration of pulmonary hypertension occurred 6 weeks after MCT injection, with some animals dying during this period because of right Heart failure. When chronically administered from Days 14-28, sildenafil significantly increased plasma cyclic guanosine monophosphate and inhibited the development of pulmonary hypertension and right Heart Hypertrophy, with preservation of gas exchange and systemic arterial pressure. A corresponding efficacy profile was also noted for long-term feeding with sildenafil from Days 28-42. Moreover, the death rate significantly decreased in those animals treated with sildenafil. We conclude that sildenafil attenuates MCT-induced pulmonary hypertension and cor pulmonale in rats.
