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Induction of Tet3-dependent Epigenetic Remodeling by Low-dose Hydralazine Attenuates Progression of Chronic Kidney Disease
Progression of chronic kidney disease remains a principal problem in clinical nephrology and there is a pressing need for novel therapeutics and biomarkers. Aberrant promoter CpG island methylation and subsequent transcriptional silencing of specific genes have emerged as contributors to progression...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4337426/ https://www.ncbi.nlm.nih.gov/pubmed/25717475 http://dx.doi.org/10.1016/j.ebiom.2014.11.005 |
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author | Tampe, Björn Tampe, Desiree Zeisberg, Elisabeth M. Müller, Gerhard A. Bechtel-Walz, Wibke Koziolek, Michael Kalluri, Raghu Zeisberg, Michael |
author_facet | Tampe, Björn Tampe, Desiree Zeisberg, Elisabeth M. Müller, Gerhard A. Bechtel-Walz, Wibke Koziolek, Michael Kalluri, Raghu Zeisberg, Michael |
author_sort | Tampe, Björn |
collection | PubMed |
description | Progression of chronic kidney disease remains a principal problem in clinical nephrology and there is a pressing need for novel therapeutics and biomarkers. Aberrant promoter CpG island methylation and subsequent transcriptional silencing of specific genes have emerged as contributors to progression of chronic kidney disease. Here, we report that transcriptional silencing of the Ras-GTP suppressor RASAL1 contributes causally to progression of kidney fibrosis and we identified that circulating methylated RASAL1 promoter DNA fragments in peripheral blood correspond with levels of intrarenal levels of RASAL1 promoter methylation and degree of fibrosis in kidney biopsies, enabling non-invasive longitudinal analysis of intrarenal CpG island methylation. Retrospective analysis of patients with hypertensive nephrosclerosis revealed that circulating methylated RASAL1 promoter DNA fragments in peripheral blood decrease with Dihydralazine treatment in patients with hypertensive nephrosclerosis, and provided evidence that low-dose Dihydralazine delays decline of excretory kidney function, whereas Dihydralazine at standard doses had no protective effect. We demonstrate that the protective effect of Dihydralazine is due to induction of endogenous Tet3/Tdg-mediated DNA-de-methylation activity reversing aberrant promoter CpG island methylation, while HIF1α induction at standard doses counterbalances its protective activity. We conclude that RASAL1 promoter methylation is a therapeutic target and a biomarker of renal fibrosis. Our study suggests that therapeutic use of low-dose Dihydralazine in patients with chronic kidney disease and fibrosis deserves further consideration. |
format | Online Article Text |
id | pubmed-4337426 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-43374262015-02-23 Induction of Tet3-dependent Epigenetic Remodeling by Low-dose Hydralazine Attenuates Progression of Chronic Kidney Disease Tampe, Björn Tampe, Desiree Zeisberg, Elisabeth M. Müller, Gerhard A. Bechtel-Walz, Wibke Koziolek, Michael Kalluri, Raghu Zeisberg, Michael EBioMedicine Original Article Progression of chronic kidney disease remains a principal problem in clinical nephrology and there is a pressing need for novel therapeutics and biomarkers. Aberrant promoter CpG island methylation and subsequent transcriptional silencing of specific genes have emerged as contributors to progression of chronic kidney disease. Here, we report that transcriptional silencing of the Ras-GTP suppressor RASAL1 contributes causally to progression of kidney fibrosis and we identified that circulating methylated RASAL1 promoter DNA fragments in peripheral blood correspond with levels of intrarenal levels of RASAL1 promoter methylation and degree of fibrosis in kidney biopsies, enabling non-invasive longitudinal analysis of intrarenal CpG island methylation. Retrospective analysis of patients with hypertensive nephrosclerosis revealed that circulating methylated RASAL1 promoter DNA fragments in peripheral blood decrease with Dihydralazine treatment in patients with hypertensive nephrosclerosis, and provided evidence that low-dose Dihydralazine delays decline of excretory kidney function, whereas Dihydralazine at standard doses had no protective effect. We demonstrate that the protective effect of Dihydralazine is due to induction of endogenous Tet3/Tdg-mediated DNA-de-methylation activity reversing aberrant promoter CpG island methylation, while HIF1α induction at standard doses counterbalances its protective activity. We conclude that RASAL1 promoter methylation is a therapeutic target and a biomarker of renal fibrosis. Our study suggests that therapeutic use of low-dose Dihydralazine in patients with chronic kidney disease and fibrosis deserves further consideration. Elsevier 2014-11-08 /pmc/articles/PMC4337426/ /pubmed/25717475 http://dx.doi.org/10.1016/j.ebiom.2014.11.005 Text en © 2014 Published by Elsevier B.V. http://creativecommons.org/licenses/by/3.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/). |
spellingShingle | Original Article Tampe, Björn Tampe, Desiree Zeisberg, Elisabeth M. Müller, Gerhard A. Bechtel-Walz, Wibke Koziolek, Michael Kalluri, Raghu Zeisberg, Michael Induction of Tet3-dependent Epigenetic Remodeling by Low-dose Hydralazine Attenuates Progression of Chronic Kidney Disease |
title | Induction of Tet3-dependent Epigenetic Remodeling by Low-dose Hydralazine Attenuates Progression of Chronic Kidney Disease |
title_full | Induction of Tet3-dependent Epigenetic Remodeling by Low-dose Hydralazine Attenuates Progression of Chronic Kidney Disease |
title_fullStr | Induction of Tet3-dependent Epigenetic Remodeling by Low-dose Hydralazine Attenuates Progression of Chronic Kidney Disease |
title_full_unstemmed | Induction of Tet3-dependent Epigenetic Remodeling by Low-dose Hydralazine Attenuates Progression of Chronic Kidney Disease |
title_short | Induction of Tet3-dependent Epigenetic Remodeling by Low-dose Hydralazine Attenuates Progression of Chronic Kidney Disease |
title_sort | induction of tet3-dependent epigenetic remodeling by low-dose hydralazine attenuates progression of chronic kidney disease |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4337426/ https://www.ncbi.nlm.nih.gov/pubmed/25717475 http://dx.doi.org/10.1016/j.ebiom.2014.11.005 |
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