Suppression of collagen IV alpha‐2 subunit by prolyl hydroxylase domain inhibition via hypoxia‐inducible factor‐1 in chronic kidney disease

Abstract Elevation of hypoxia‐inducible factor 1 protein has been shown to be protective in acute kidney injury and HIF1α enhancing drug therapies are currently in clinical trials for the treatment of anemia of chronic kidney disease. Despite its benefits, long‐term HIF1 elevation seems to be associ...

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Autores principales:	Mohammad Sanaei‐Ardekani, Shyreen Kamal, Whitney Handy, Sidrah Alam, Aya Salaheldin, Anderson Moore, Shahrzad Movafagh
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	anemia CKD collagen IV hypoxia inducible factor‐1 prolyl hydroxylse inhibitors tubular fibrosis Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/2ac75860d8e74069910231c81b47907e
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spelling	oai:doaj.org-article:2ac75860d8e74069910231c81b47907e2021-11-16T13:45:55ZSuppression of collagen IV alpha‐2 subunit by prolyl hydroxylase domain inhibition via hypoxia‐inducible factor‐1 in chronic kidney disease2052-170710.1002/prp2.872https://doaj.org/article/2ac75860d8e74069910231c81b47907e2021-10-01T00:00:00Zhttps://doi.org/10.1002/prp2.872https://doaj.org/toc/2052-1707Abstract Elevation of hypoxia‐inducible factor 1 protein has been shown to be protective in acute kidney injury and HIF1α enhancing drug therapies are currently in clinical trials for the treatment of anemia of chronic kidney disease. Despite its benefits, long‐term HIF1 elevation seems to be associated with additional effects in the kidneys such as tubulointerstitial fibrosis. To better understand the effects of prolonged HIF1 exposure, assessment of baseline and post‐therapy levels of HIF1α and other related biomarkers is essential. In this study, we assessed the effect of HIF1α enhancement using prolyl hydroxylase inhibitor (PHD‐I) DMOG, on a key profibrotic marker of kidney disease. In specific, we examined the change in expression of Collagen 4 subunit A2 in cultured urinary cells of CKD patients pre and post 24‐hour exposure to 1mM DMOG. Our results show that besides HIF1α enhancement, COL4A2 protein is suppressed in presence of DMOG. To determine if this effect is mediated by HIF1, we used HIF1α gene silencing in HEK293 cells and examined the effect of DMOG on protein and gene expression of COL4A2 post 24‐hour exposure. We showed that silencing HIF1α reverses and amplifies the expression of COL4A2 in HEK293 cells. Our data suggest that HIF1 directly regulates the expression of COL4A2 in kidney cells and that HIF1α enhancing therapy has suppressive effects on COL4A2 that may be clinically relevant and must be considered in determining the safety and efficacy of these drugs in the treatment of anemia.Mohammad Sanaei‐ArdekaniShyreen KamalWhitney HandySidrah AlamAya SalaheldinAnderson MooreShahrzad MovafaghWileyarticleanemiaCKDcollagen IVhypoxia inducible factor‐1prolyl hydroxylse inhibitorstubular fibrosisTherapeutics. PharmacologyRM1-950ENPharmacology Research & Perspectives, Vol 9, Iss 5, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	anemia CKD collagen IV hypoxia inducible factor‐1 prolyl hydroxylse inhibitors tubular fibrosis Therapeutics. Pharmacology RM1-950
spellingShingle	anemia CKD collagen IV hypoxia inducible factor‐1 prolyl hydroxylse inhibitors tubular fibrosis Therapeutics. Pharmacology RM1-950 Mohammad Sanaei‐Ardekani Shyreen Kamal Whitney Handy Sidrah Alam Aya Salaheldin Anderson Moore Shahrzad Movafagh Suppression of collagen IV alpha‐2 subunit by prolyl hydroxylase domain inhibition via hypoxia‐inducible factor‐1 in chronic kidney disease
description	Abstract Elevation of hypoxia‐inducible factor 1 protein has been shown to be protective in acute kidney injury and HIF1α enhancing drug therapies are currently in clinical trials for the treatment of anemia of chronic kidney disease. Despite its benefits, long‐term HIF1 elevation seems to be associated with additional effects in the kidneys such as tubulointerstitial fibrosis. To better understand the effects of prolonged HIF1 exposure, assessment of baseline and post‐therapy levels of HIF1α and other related biomarkers is essential. In this study, we assessed the effect of HIF1α enhancement using prolyl hydroxylase inhibitor (PHD‐I) DMOG, on a key profibrotic marker of kidney disease. In specific, we examined the change in expression of Collagen 4 subunit A2 in cultured urinary cells of CKD patients pre and post 24‐hour exposure to 1mM DMOG. Our results show that besides HIF1α enhancement, COL4A2 protein is suppressed in presence of DMOG. To determine if this effect is mediated by HIF1, we used HIF1α gene silencing in HEK293 cells and examined the effect of DMOG on protein and gene expression of COL4A2 post 24‐hour exposure. We showed that silencing HIF1α reverses and amplifies the expression of COL4A2 in HEK293 cells. Our data suggest that HIF1 directly regulates the expression of COL4A2 in kidney cells and that HIF1α enhancing therapy has suppressive effects on COL4A2 that may be clinically relevant and must be considered in determining the safety and efficacy of these drugs in the treatment of anemia.
format	article
author	Mohammad Sanaei‐Ardekani Shyreen Kamal Whitney Handy Sidrah Alam Aya Salaheldin Anderson Moore Shahrzad Movafagh
author_facet	Mohammad Sanaei‐Ardekani Shyreen Kamal Whitney Handy Sidrah Alam Aya Salaheldin Anderson Moore Shahrzad Movafagh
author_sort	Mohammad Sanaei‐Ardekani
title	Suppression of collagen IV alpha‐2 subunit by prolyl hydroxylase domain inhibition via hypoxia‐inducible factor‐1 in chronic kidney disease
title_short	Suppression of collagen IV alpha‐2 subunit by prolyl hydroxylase domain inhibition via hypoxia‐inducible factor‐1 in chronic kidney disease
title_full	Suppression of collagen IV alpha‐2 subunit by prolyl hydroxylase domain inhibition via hypoxia‐inducible factor‐1 in chronic kidney disease
title_fullStr	Suppression of collagen IV alpha‐2 subunit by prolyl hydroxylase domain inhibition via hypoxia‐inducible factor‐1 in chronic kidney disease
title_full_unstemmed	Suppression of collagen IV alpha‐2 subunit by prolyl hydroxylase domain inhibition via hypoxia‐inducible factor‐1 in chronic kidney disease
title_sort	suppression of collagen iv alpha‐2 subunit by prolyl hydroxylase domain inhibition via hypoxia‐inducible factor‐1 in chronic kidney disease
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/2ac75860d8e74069910231c81b47907e
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Suppression of collagen IV alpha‐2 subunit by prolyl hydroxylase domain inhibition via hypoxia‐inducible factor‐1 in chronic kidney disease

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