A small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase improves obesity, nephropathy and cardiomyopathy in obese ZSF1 rats.

Prolyl hydroxylase (PH) enzymes control the degradation of hypoxia-inducible factor (HIF), a transcription factor known to regulate erythropoiesis, angiogenesis, glucose metabolism, cell proliferation, and apoptosis. HIF-PH inhibitors (HIF-PHIs) correct anemia in patients with renal disease and in a...

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Autores principales:	Pierre E Signore, Guangjie Guo, Zhihua Wei, Weihua Zhang, Al Lin, Ughetta Del Balzo
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/29b1b5bc4f374084a6a0d5b79eeb70af
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spelling	oai:doaj.org-article:29b1b5bc4f374084a6a0d5b79eeb70af2021-12-02T20:18:53ZA small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase improves obesity, nephropathy and cardiomyopathy in obese ZSF1 rats.1932-620310.1371/journal.pone.0255022https://doaj.org/article/29b1b5bc4f374084a6a0d5b79eeb70af2021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0255022https://doaj.org/toc/1932-6203Prolyl hydroxylase (PH) enzymes control the degradation of hypoxia-inducible factor (HIF), a transcription factor known to regulate erythropoiesis, angiogenesis, glucose metabolism, cell proliferation, and apoptosis. HIF-PH inhibitors (HIF-PHIs) correct anemia in patients with renal disease and in animal models of anemia and kidney disease. However, the effects of HIF-PHIs on comorbidities associated with kidney disease remain largely unknown. We evaluated the effects of the HIF-PHI FG-2216 in obese ZSF1 (Ob-ZSF1) rats, an established model of kidney failure with metabolic syndrome. Following unilateral nephrectomy (Nx) at 8 weeks of age, rats were treated with 40 mg/kg FG-2216 or vehicle by oral gavage three times per week for up to 18 weeks. FG-2216 corrected blood hemoglobin levels and improved kidney function and histopathology in Nx-Ob-ZSF1 rats by increasing the glomerular filtration rate, decreasing proteinuria, and reducing peritubular fibrosis, tubular damage, glomerulosclerosis and mesangial expansion. FG-2216 increased renal glucose excretion and decreased body weight, fat pad weight, and serum cholesterol in Nx-Ob-ZSF1 rats. Additionally, FG-2216 corrected hypertension, improved diastolic and systolic heart function, and reduced cardiac hypertrophy and fibrosis. In conclusion, the HIF-PHI FG-2216 improved renal and cardiovascular outcomes, and reduced obesity in a rat model of kidney disease with metabolic syndrome. Thus, in addition to correcting anemia, HIF-PHIs may provide renal and cardiac protection to patients suffering from kidney disease with metabolic syndrome.Pierre E SignoreGuangjie GuoZhihua WeiWeihua ZhangAl LinUghetta Del BalzoPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 8, p e0255022 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Pierre E Signore Guangjie Guo Zhihua Wei Weihua Zhang Al Lin Ughetta Del Balzo A small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase improves obesity, nephropathy and cardiomyopathy in obese ZSF1 rats.
description	Prolyl hydroxylase (PH) enzymes control the degradation of hypoxia-inducible factor (HIF), a transcription factor known to regulate erythropoiesis, angiogenesis, glucose metabolism, cell proliferation, and apoptosis. HIF-PH inhibitors (HIF-PHIs) correct anemia in patients with renal disease and in animal models of anemia and kidney disease. However, the effects of HIF-PHIs on comorbidities associated with kidney disease remain largely unknown. We evaluated the effects of the HIF-PHI FG-2216 in obese ZSF1 (Ob-ZSF1) rats, an established model of kidney failure with metabolic syndrome. Following unilateral nephrectomy (Nx) at 8 weeks of age, rats were treated with 40 mg/kg FG-2216 or vehicle by oral gavage three times per week for up to 18 weeks. FG-2216 corrected blood hemoglobin levels and improved kidney function and histopathology in Nx-Ob-ZSF1 rats by increasing the glomerular filtration rate, decreasing proteinuria, and reducing peritubular fibrosis, tubular damage, glomerulosclerosis and mesangial expansion. FG-2216 increased renal glucose excretion and decreased body weight, fat pad weight, and serum cholesterol in Nx-Ob-ZSF1 rats. Additionally, FG-2216 corrected hypertension, improved diastolic and systolic heart function, and reduced cardiac hypertrophy and fibrosis. In conclusion, the HIF-PHI FG-2216 improved renal and cardiovascular outcomes, and reduced obesity in a rat model of kidney disease with metabolic syndrome. Thus, in addition to correcting anemia, HIF-PHIs may provide renal and cardiac protection to patients suffering from kidney disease with metabolic syndrome.
format	article
author	Pierre E Signore Guangjie Guo Zhihua Wei Weihua Zhang Al Lin Ughetta Del Balzo
author_facet	Pierre E Signore Guangjie Guo Zhihua Wei Weihua Zhang Al Lin Ughetta Del Balzo
author_sort	Pierre E Signore
title	A small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase improves obesity, nephropathy and cardiomyopathy in obese ZSF1 rats.
title_short	A small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase improves obesity, nephropathy and cardiomyopathy in obese ZSF1 rats.
title_full	A small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase improves obesity, nephropathy and cardiomyopathy in obese ZSF1 rats.
title_fullStr	A small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase improves obesity, nephropathy and cardiomyopathy in obese ZSF1 rats.
title_full_unstemmed	A small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase improves obesity, nephropathy and cardiomyopathy in obese ZSF1 rats.
title_sort	small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase improves obesity, nephropathy and cardiomyopathy in obese zsf1 rats.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/29b1b5bc4f374084a6a0d5b79eeb70af
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A small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase improves obesity, nephropathy and cardiomyopathy in obese ZSF1 rats.

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