Glomerular endothelial cell heterogeneity in Alport syndrome

Abstract Glomerular endothelial cells (GEC) are a crucial component of the glomerular physiology and their damage contributes to the progression of chronic kidney diseases. How GEC affect the pathology of Alport syndrome (AS) however, is unclear. We characterized GEC from wild type (WT) and col4α5 k...

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Autores principales:	Hasmik Soloyan, Matthew Thornton, Valentina Villani, Patrick Khatchadourian, Paolo Cravedi, Andrea Angeletti, Brendan Grubbs, Roger De Filippo, Laura Perin, Sargis Sedrakyan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a65b9cc1a4f24bcc8215f165c1aea6a8
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spelling	oai:doaj.org-article:a65b9cc1a4f24bcc8215f165c1aea6a82021-12-02T16:24:49ZGlomerular endothelial cell heterogeneity in Alport syndrome10.1038/s41598-020-67588-02045-2322https://doaj.org/article/a65b9cc1a4f24bcc8215f165c1aea6a82020-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-67588-0https://doaj.org/toc/2045-2322Abstract Glomerular endothelial cells (GEC) are a crucial component of the glomerular physiology and their damage contributes to the progression of chronic kidney diseases. How GEC affect the pathology of Alport syndrome (AS) however, is unclear. We characterized GEC from wild type (WT) and col4α5 knockout AS mice, a hereditary disorder characterized by progressive renal failure. We used endothelial-specific Tek-tdTomato reporter mice to isolate GEC by FACS and performed transcriptome analysis on them from WT and AS mice, followed by in vitro functional assays and confocal and intravital imaging studies. Biopsies from patients with chronic kidney disease, including AS were compared with our findings in mice. We identified two subpopulations of GEC (dimtdT and brighttdT) based on the fluorescence intensity of the TektdT signal. In AS mice, the brighttdT cell number increased and presented differential expression of endothelial markers compared to WT. RNA-seq analysis revealed differences in the immune and metabolic signaling pathways. In AS mice, dimtdT and brighttdT cells had different expression profiles of matrix-associated genes (Svep1, Itgβ6), metabolic activity (Apom, Pgc1α) and immune modulation (Apelin, Icam1) compared to WT mice. We confirmed a new pro-inflammatory role of Apelin in AS mice and in cultured human GEC. Gene modulations were identified comparable to the biopsies from patients with AS and focal segmental glomerulosclerosis, possibly indicating that the same mechanisms apply to humans. We report the presence of two GEC subpopulations that differ between AS and healthy mice or humans. This finding paves the way to a better understanding of the pathogenic role of GEC in AS progression and could lead to novel therapeutic targets.Hasmik SoloyanMatthew ThorntonValentina VillaniPatrick KhatchadourianPaolo CravediAndrea AngelettiBrendan GrubbsRoger De FilippoLaura PerinSargis SedrakyanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-18 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hasmik Soloyan Matthew Thornton Valentina Villani Patrick Khatchadourian Paolo Cravedi Andrea Angeletti Brendan Grubbs Roger De Filippo Laura Perin Sargis Sedrakyan Glomerular endothelial cell heterogeneity in Alport syndrome
description	Abstract Glomerular endothelial cells (GEC) are a crucial component of the glomerular physiology and their damage contributes to the progression of chronic kidney diseases. How GEC affect the pathology of Alport syndrome (AS) however, is unclear. We characterized GEC from wild type (WT) and col4α5 knockout AS mice, a hereditary disorder characterized by progressive renal failure. We used endothelial-specific Tek-tdTomato reporter mice to isolate GEC by FACS and performed transcriptome analysis on them from WT and AS mice, followed by in vitro functional assays and confocal and intravital imaging studies. Biopsies from patients with chronic kidney disease, including AS were compared with our findings in mice. We identified two subpopulations of GEC (dimtdT and brighttdT) based on the fluorescence intensity of the TektdT signal. In AS mice, the brighttdT cell number increased and presented differential expression of endothelial markers compared to WT. RNA-seq analysis revealed differences in the immune and metabolic signaling pathways. In AS mice, dimtdT and brighttdT cells had different expression profiles of matrix-associated genes (Svep1, Itgβ6), metabolic activity (Apom, Pgc1α) and immune modulation (Apelin, Icam1) compared to WT mice. We confirmed a new pro-inflammatory role of Apelin in AS mice and in cultured human GEC. Gene modulations were identified comparable to the biopsies from patients with AS and focal segmental glomerulosclerosis, possibly indicating that the same mechanisms apply to humans. We report the presence of two GEC subpopulations that differ between AS and healthy mice or humans. This finding paves the way to a better understanding of the pathogenic role of GEC in AS progression and could lead to novel therapeutic targets.
format	article
author	Hasmik Soloyan Matthew Thornton Valentina Villani Patrick Khatchadourian Paolo Cravedi Andrea Angeletti Brendan Grubbs Roger De Filippo Laura Perin Sargis Sedrakyan
author_facet	Hasmik Soloyan Matthew Thornton Valentina Villani Patrick Khatchadourian Paolo Cravedi Andrea Angeletti Brendan Grubbs Roger De Filippo Laura Perin Sargis Sedrakyan
author_sort	Hasmik Soloyan
title	Glomerular endothelial cell heterogeneity in Alport syndrome
title_short	Glomerular endothelial cell heterogeneity in Alport syndrome
title_full	Glomerular endothelial cell heterogeneity in Alport syndrome
title_fullStr	Glomerular endothelial cell heterogeneity in Alport syndrome
title_full_unstemmed	Glomerular endothelial cell heterogeneity in Alport syndrome
title_sort	glomerular endothelial cell heterogeneity in alport syndrome
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/a65b9cc1a4f24bcc8215f165c1aea6a8
work_keys_str_mv	AT hasmiksoloyan glomerularendothelialcellheterogeneityinalportsyndrome AT matthewthornton glomerularendothelialcellheterogeneityinalportsyndrome AT valentinavillani glomerularendothelialcellheterogeneityinalportsyndrome AT patrickkhatchadourian glomerularendothelialcellheterogeneityinalportsyndrome AT paolocravedi glomerularendothelialcellheterogeneityinalportsyndrome AT andreaangeletti glomerularendothelialcellheterogeneityinalportsyndrome AT brendangrubbs glomerularendothelialcellheterogeneityinalportsyndrome AT rogerdefilippo glomerularendothelialcellheterogeneityinalportsyndrome AT lauraperin glomerularendothelialcellheterogeneityinalportsyndrome AT sargissedrakyan glomerularendothelialcellheterogeneityinalportsyndrome
_version_	1718384128811859968

Glomerular endothelial cell heterogeneity in Alport syndrome

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