Vegfa promoter gene hypermethylation at HIF1α binding site is an early contributor to CKD progression after renal ischemia

Abstract Chronic hypoxia is a major contributor to Chronic Kidney Disease (CKD) after Acute Kidney Injury (AKI). However, the temporal relation between the acute insult and maladaptive renal response to hypoxia remains unclear. In this study, we analyzed the time-course of renal hemodynamics, oxidat...

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Autores principales:	Andrea Sánchez-Navarro, Rosalba Pérez-Villalva, Adrián Rafael Murillo-de-Ozores, Miguel Ángel Martínez-Rojas, Jesús Rafael Rodríguez‐Aguilera, Norma González, María Castañeda-Bueno, Gerardo Gamba, Félix Recillas-Targa, Norma A. Bobadilla
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b817cd98367b4fcab3c380f87c019862
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spelling	oai:doaj.org-article:b817cd98367b4fcab3c380f87c0198622021-12-02T18:27:48ZVegfa promoter gene hypermethylation at HIF1α binding site is an early contributor to CKD progression after renal ischemia10.1038/s41598-021-88000-52045-2322https://doaj.org/article/b817cd98367b4fcab3c380f87c0198622021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88000-5https://doaj.org/toc/2045-2322Abstract Chronic hypoxia is a major contributor to Chronic Kidney Disease (CKD) after Acute Kidney Injury (AKI). However, the temporal relation between the acute insult and maladaptive renal response to hypoxia remains unclear. In this study, we analyzed the time-course of renal hemodynamics, oxidative stress, inflammation, and fibrosis, as well as epigenetic modifications, with focus on HIF1α/VEGF signaling, in the AKI to CKD transition. Sham-operated, right nephrectomy (UNx), and UNx plus renal ischemia (IR + UNx) groups of rats were included and studied at 1, 2, 3, or 4 months. The IR + UNx group developed CKD characterized by progressive proteinuria, renal dysfunction, tubular proliferation, and fibrosis. At first month post-ischemia, there was a twofold significant increase in oxidative stress and reduction in global DNA methylation that was maintained throughout the study. Hif1α and Vegfa expression were depressed in the first and second-months post-ischemia, and then Hif1α but not Vegfa expression was recovered. Interestingly, hypermethylation of the Vegfa promoter gene at the HIF1α binding site was found, since early stages of the CKD progression. Our findings suggest that renal hypoperfusion, inefficient hypoxic response, increased oxidative stress, DNA hypomethylation, and, Vegfa promoter gene hypermethylation at HIF1α binding site, are early determinants of AKI-to-CKD transition.Andrea Sánchez-NavarroRosalba Pérez-VillalvaAdrián Rafael Murillo-de-OzoresMiguel Ángel Martínez-RojasJesús Rafael Rodríguez‐AguileraNorma GonzálezMaría Castañeda-BuenoGerardo GambaFélix Recillas-TargaNorma A. BobadillaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Andrea Sánchez-Navarro Rosalba Pérez-Villalva Adrián Rafael Murillo-de-Ozores Miguel Ángel Martínez-Rojas Jesús Rafael Rodríguez‐Aguilera Norma González María Castañeda-Bueno Gerardo Gamba Félix Recillas-Targa Norma A. Bobadilla Vegfa promoter gene hypermethylation at HIF1α binding site is an early contributor to CKD progression after renal ischemia
description	Abstract Chronic hypoxia is a major contributor to Chronic Kidney Disease (CKD) after Acute Kidney Injury (AKI). However, the temporal relation between the acute insult and maladaptive renal response to hypoxia remains unclear. In this study, we analyzed the time-course of renal hemodynamics, oxidative stress, inflammation, and fibrosis, as well as epigenetic modifications, with focus on HIF1α/VEGF signaling, in the AKI to CKD transition. Sham-operated, right nephrectomy (UNx), and UNx plus renal ischemia (IR + UNx) groups of rats were included and studied at 1, 2, 3, or 4 months. The IR + UNx group developed CKD characterized by progressive proteinuria, renal dysfunction, tubular proliferation, and fibrosis. At first month post-ischemia, there was a twofold significant increase in oxidative stress and reduction in global DNA methylation that was maintained throughout the study. Hif1α and Vegfa expression were depressed in the first and second-months post-ischemia, and then Hif1α but not Vegfa expression was recovered. Interestingly, hypermethylation of the Vegfa promoter gene at the HIF1α binding site was found, since early stages of the CKD progression. Our findings suggest that renal hypoperfusion, inefficient hypoxic response, increased oxidative stress, DNA hypomethylation, and, Vegfa promoter gene hypermethylation at HIF1α binding site, are early determinants of AKI-to-CKD transition.
format	article
author	Andrea Sánchez-Navarro Rosalba Pérez-Villalva Adrián Rafael Murillo-de-Ozores Miguel Ángel Martínez-Rojas Jesús Rafael Rodríguez‐Aguilera Norma González María Castañeda-Bueno Gerardo Gamba Félix Recillas-Targa Norma A. Bobadilla
author_facet	Andrea Sánchez-Navarro Rosalba Pérez-Villalva Adrián Rafael Murillo-de-Ozores Miguel Ángel Martínez-Rojas Jesús Rafael Rodríguez‐Aguilera Norma González María Castañeda-Bueno Gerardo Gamba Félix Recillas-Targa Norma A. Bobadilla
author_sort	Andrea Sánchez-Navarro
title	Vegfa promoter gene hypermethylation at HIF1α binding site is an early contributor to CKD progression after renal ischemia
title_short	Vegfa promoter gene hypermethylation at HIF1α binding site is an early contributor to CKD progression after renal ischemia
title_full	Vegfa promoter gene hypermethylation at HIF1α binding site is an early contributor to CKD progression after renal ischemia
title_fullStr	Vegfa promoter gene hypermethylation at HIF1α binding site is an early contributor to CKD progression after renal ischemia
title_full_unstemmed	Vegfa promoter gene hypermethylation at HIF1α binding site is an early contributor to CKD progression after renal ischemia
title_sort	vegfa promoter gene hypermethylation at hif1α binding site is an early contributor to ckd progression after renal ischemia
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/b817cd98367b4fcab3c380f87c019862
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Vegfa promoter gene hypermethylation at HIF1α binding site is an early contributor to CKD progression after renal ischemia

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