Cargando…
MicroRNA-184 is a downstream effector of albuminuria driving renal fibrosis in rats with diabetic nephropathy
AIMS/HYPOTHESIS: Renal fibrosis is a common complication of diabetic nephropathy and is a major cause of end-stage renal disease. Despite the suggested link between renal fibrosis and microRNA (miRNA) dysregulation in diabetic nephropathy, the identification of the specific miRNAs involved is still...
Autores principales: | , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5423990/ https://www.ncbi.nlm.nih.gov/pubmed/28364255 http://dx.doi.org/10.1007/s00125-017-4248-9 |
_version_ | 1783235040831864832 |
---|---|
author | Zanchi, Cristina Macconi, Daniela Trionfini, Piera Tomasoni, Susanna Rottoli, Daniela Locatelli, Monica Rudnicki, Michael Vandesompele, Jo Mestdagh, Pieter Remuzzi, Giuseppe Benigni, Ariela Zoja, Carlamaria |
author_facet | Zanchi, Cristina Macconi, Daniela Trionfini, Piera Tomasoni, Susanna Rottoli, Daniela Locatelli, Monica Rudnicki, Michael Vandesompele, Jo Mestdagh, Pieter Remuzzi, Giuseppe Benigni, Ariela Zoja, Carlamaria |
author_sort | Zanchi, Cristina |
collection | PubMed |
description | AIMS/HYPOTHESIS: Renal fibrosis is a common complication of diabetic nephropathy and is a major cause of end-stage renal disease. Despite the suggested link between renal fibrosis and microRNA (miRNA) dysregulation in diabetic nephropathy, the identification of the specific miRNAs involved is still incomplete. The aim of this study was to investigate miRNA profiles in the diabetic kidney and to identify potential downstream targets implicated in renal fibrosis. METHODS: miRNA expression profiling was investigated in the kidneys of 8-month-old Zucker diabetic fatty (ZDF) rats during overt nephropathy. Localisation of the most upregulated miRNA was established by in situ hybridisation. The candidate miRNA target was identified by in silico analysis and its expression documented in the diabetic kidney associated with fibrotic markers. Cultured tubule cells served to assess which of the profibrogenic stimuli acted as a trigger for the overexpressed miRNA, and to investigate underlying epigenetic mechanisms. RESULTS: In ZDF rats, miR-184 showed the strongest differential upregulation compared with lean rats (18-fold). Tubular localisation of miR-184 was associated with reduced expression of lipid phosphate phosphatase 3 (LPP3) and collagen accumulation. Transfection of NRK-52E cells with miR-184 mimic reduced LPP3, promoting a profibrotic phenotype. Albumin was a major trigger of miR-184 expression. Anti-miR-184 counteracted albumin-induced LPP3 downregulation and overexpression of plasminogen activator inhibitor-1. In ZDF rats, ACE-inhibitor treatment limited albuminuria and reduced miR-184, with tubular LPP3 preservation and tubulointerstitial fibrosis amelioration. Albumin-induced miR-184 expression in tubule cells was epigenetically regulated through DNA demethylation and histone lysine acetylation and was accompanied by binding of NF-κB p65 subunit to miR-184 promoter. CONCLUSIONS/INTERPRETATION: These results suggest that miR-184 may act as a downstream effector of albuminuria through LPP3 to promote tubulointerstitial fibrosis, and offer the rationale to investigate whether targeting miR-184 in association with albuminuria-lowering drugs may be a new strategy to achieve fully anti-fibrotic effects in diabetic nephropathy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00125-017-4248-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users. |
format | Online Article Text |
id | pubmed-5423990 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-54239902017-05-25 MicroRNA-184 is a downstream effector of albuminuria driving renal fibrosis in rats with diabetic nephropathy Zanchi, Cristina Macconi, Daniela Trionfini, Piera Tomasoni, Susanna Rottoli, Daniela Locatelli, Monica Rudnicki, Michael Vandesompele, Jo Mestdagh, Pieter Remuzzi, Giuseppe Benigni, Ariela Zoja, Carlamaria Diabetologia Article AIMS/HYPOTHESIS: Renal fibrosis is a common complication of diabetic nephropathy and is a major cause of end-stage renal disease. Despite the suggested link between renal fibrosis and microRNA (miRNA) dysregulation in diabetic nephropathy, the identification of the specific miRNAs involved is still incomplete. The aim of this study was to investigate miRNA profiles in the diabetic kidney and to identify potential downstream targets implicated in renal fibrosis. METHODS: miRNA expression profiling was investigated in the kidneys of 8-month-old Zucker diabetic fatty (ZDF) rats during overt nephropathy. Localisation of the most upregulated miRNA was established by in situ hybridisation. The candidate miRNA target was identified by in silico analysis and its expression documented in the diabetic kidney associated with fibrotic markers. Cultured tubule cells served to assess which of the profibrogenic stimuli acted as a trigger for the overexpressed miRNA, and to investigate underlying epigenetic mechanisms. RESULTS: In ZDF rats, miR-184 showed the strongest differential upregulation compared with lean rats (18-fold). Tubular localisation of miR-184 was associated with reduced expression of lipid phosphate phosphatase 3 (LPP3) and collagen accumulation. Transfection of NRK-52E cells with miR-184 mimic reduced LPP3, promoting a profibrotic phenotype. Albumin was a major trigger of miR-184 expression. Anti-miR-184 counteracted albumin-induced LPP3 downregulation and overexpression of plasminogen activator inhibitor-1. In ZDF rats, ACE-inhibitor treatment limited albuminuria and reduced miR-184, with tubular LPP3 preservation and tubulointerstitial fibrosis amelioration. Albumin-induced miR-184 expression in tubule cells was epigenetically regulated through DNA demethylation and histone lysine acetylation and was accompanied by binding of NF-κB p65 subunit to miR-184 promoter. CONCLUSIONS/INTERPRETATION: These results suggest that miR-184 may act as a downstream effector of albuminuria through LPP3 to promote tubulointerstitial fibrosis, and offer the rationale to investigate whether targeting miR-184 in association with albuminuria-lowering drugs may be a new strategy to achieve fully anti-fibrotic effects in diabetic nephropathy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00125-017-4248-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users. Springer Berlin Heidelberg 2017-03-31 2017 /pmc/articles/PMC5423990/ /pubmed/28364255 http://dx.doi.org/10.1007/s00125-017-4248-9 Text en © The Author(s) 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. |
spellingShingle | Article Zanchi, Cristina Macconi, Daniela Trionfini, Piera Tomasoni, Susanna Rottoli, Daniela Locatelli, Monica Rudnicki, Michael Vandesompele, Jo Mestdagh, Pieter Remuzzi, Giuseppe Benigni, Ariela Zoja, Carlamaria MicroRNA-184 is a downstream effector of albuminuria driving renal fibrosis in rats with diabetic nephropathy |
title | MicroRNA-184 is a downstream effector of albuminuria driving renal fibrosis in rats with diabetic nephropathy |
title_full | MicroRNA-184 is a downstream effector of albuminuria driving renal fibrosis in rats with diabetic nephropathy |
title_fullStr | MicroRNA-184 is a downstream effector of albuminuria driving renal fibrosis in rats with diabetic nephropathy |
title_full_unstemmed | MicroRNA-184 is a downstream effector of albuminuria driving renal fibrosis in rats with diabetic nephropathy |
title_short | MicroRNA-184 is a downstream effector of albuminuria driving renal fibrosis in rats with diabetic nephropathy |
title_sort | microrna-184 is a downstream effector of albuminuria driving renal fibrosis in rats with diabetic nephropathy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5423990/ https://www.ncbi.nlm.nih.gov/pubmed/28364255 http://dx.doi.org/10.1007/s00125-017-4248-9 |
work_keys_str_mv | AT zanchicristina microrna184isadownstreameffectorofalbuminuriadrivingrenalfibrosisinratswithdiabeticnephropathy AT macconidaniela microrna184isadownstreameffectorofalbuminuriadrivingrenalfibrosisinratswithdiabeticnephropathy AT trionfinipiera microrna184isadownstreameffectorofalbuminuriadrivingrenalfibrosisinratswithdiabeticnephropathy AT tomasonisusanna microrna184isadownstreameffectorofalbuminuriadrivingrenalfibrosisinratswithdiabeticnephropathy AT rottolidaniela microrna184isadownstreameffectorofalbuminuriadrivingrenalfibrosisinratswithdiabeticnephropathy AT locatellimonica microrna184isadownstreameffectorofalbuminuriadrivingrenalfibrosisinratswithdiabeticnephropathy AT rudnickimichael microrna184isadownstreameffectorofalbuminuriadrivingrenalfibrosisinratswithdiabeticnephropathy AT vandesompelejo microrna184isadownstreameffectorofalbuminuriadrivingrenalfibrosisinratswithdiabeticnephropathy AT mestdaghpieter microrna184isadownstreameffectorofalbuminuriadrivingrenalfibrosisinratswithdiabeticnephropathy AT remuzzigiuseppe microrna184isadownstreameffectorofalbuminuriadrivingrenalfibrosisinratswithdiabeticnephropathy AT benigniariela microrna184isadownstreameffectorofalbuminuriadrivingrenalfibrosisinratswithdiabeticnephropathy AT zojacarlamaria microrna184isadownstreameffectorofalbuminuriadrivingrenalfibrosisinratswithdiabeticnephropathy |