Early involvement of cellular stress and inflammatory signals in the pathogenesis of tubulointerstitial kidney disease due to UMOD mutations

Abstract Autosomal dominant tubulointerstitial kidney disease (ADTKD) is an inherited disorder that causes progressive kidney damage and renal failure. Mutations in the UMOD gene, encoding uromodulin, lead to ADTKD-UMOD related. Uromodulin is a GPI-anchored protein exclusively produced by epithelial...

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Autores principales:	Matteo Trudu, Celine Schaeffer, Michela Riba, Masami Ikehata, Paola Brambilla, Piergiorgio Messa, Filippo Martinelli-Boneschi, Maria Pia Rastaldi, Luca Rampoldi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/dad07a09c2784d458c8b05679b0804dd
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spelling	oai:doaj.org-article:dad07a09c2784d458c8b05679b0804dd2021-12-02T11:53:09ZEarly involvement of cellular stress and inflammatory signals in the pathogenesis of tubulointerstitial kidney disease due to UMOD mutations10.1038/s41598-017-07804-62045-2322https://doaj.org/article/dad07a09c2784d458c8b05679b0804dd2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-07804-6https://doaj.org/toc/2045-2322Abstract Autosomal dominant tubulointerstitial kidney disease (ADTKD) is an inherited disorder that causes progressive kidney damage and renal failure. Mutations in the UMOD gene, encoding uromodulin, lead to ADTKD-UMOD related. Uromodulin is a GPI-anchored protein exclusively produced by epithelial cells of the thick ascending limb of Henle’s loop. It is released in the tubular lumen after proteolytic cleavage and represents the most abundant protein in human urine in physiological condition. We previously generated and characterized a transgenic mouse model expressing mutant uromodulin (Tg UmodC147W) that recapitulates the main features of ATDKD-UMOD. While several studies clearly demonstrated that mutated uromodulin accumulates in endoplasmic reticulum, the mechanisms that lead to renal damage are not fully understood. In our work, we used kidney transcriptional profiling to identify early events of pathogenesis in the kidneys of Tg UmodC147W mice. Our results demonstrate up-regulation of inflammation and fibrosis and down-regulation of lipid metabolism in young Tg UmodC147W mice, before any functional or histological evidence of kidney damage. We also show that pro-inflammatory signals precede fibrosis onset and are already present in the first week after birth. Early induction of inflammation is likely relevant for ADTKD-UMOD pathogenesis and related pathways can be envisaged as possible novel targets for therapeutic intervention.Matteo TruduCeline SchaefferMichela RibaMasami IkehataPaola BrambillaPiergiorgio MessaFilippo Martinelli-BoneschiMaria Pia RastaldiLuca RampoldiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-16 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Matteo Trudu Celine Schaeffer Michela Riba Masami Ikehata Paola Brambilla Piergiorgio Messa Filippo Martinelli-Boneschi Maria Pia Rastaldi Luca Rampoldi Early involvement of cellular stress and inflammatory signals in the pathogenesis of tubulointerstitial kidney disease due to UMOD mutations
description	Abstract Autosomal dominant tubulointerstitial kidney disease (ADTKD) is an inherited disorder that causes progressive kidney damage and renal failure. Mutations in the UMOD gene, encoding uromodulin, lead to ADTKD-UMOD related. Uromodulin is a GPI-anchored protein exclusively produced by epithelial cells of the thick ascending limb of Henle’s loop. It is released in the tubular lumen after proteolytic cleavage and represents the most abundant protein in human urine in physiological condition. We previously generated and characterized a transgenic mouse model expressing mutant uromodulin (Tg UmodC147W) that recapitulates the main features of ATDKD-UMOD. While several studies clearly demonstrated that mutated uromodulin accumulates in endoplasmic reticulum, the mechanisms that lead to renal damage are not fully understood. In our work, we used kidney transcriptional profiling to identify early events of pathogenesis in the kidneys of Tg UmodC147W mice. Our results demonstrate up-regulation of inflammation and fibrosis and down-regulation of lipid metabolism in young Tg UmodC147W mice, before any functional or histological evidence of kidney damage. We also show that pro-inflammatory signals precede fibrosis onset and are already present in the first week after birth. Early induction of inflammation is likely relevant for ADTKD-UMOD pathogenesis and related pathways can be envisaged as possible novel targets for therapeutic intervention.
format	article
author	Matteo Trudu Celine Schaeffer Michela Riba Masami Ikehata Paola Brambilla Piergiorgio Messa Filippo Martinelli-Boneschi Maria Pia Rastaldi Luca Rampoldi
author_facet	Matteo Trudu Celine Schaeffer Michela Riba Masami Ikehata Paola Brambilla Piergiorgio Messa Filippo Martinelli-Boneschi Maria Pia Rastaldi Luca Rampoldi
author_sort	Matteo Trudu
title	Early involvement of cellular stress and inflammatory signals in the pathogenesis of tubulointerstitial kidney disease due to UMOD mutations
title_short	Early involvement of cellular stress and inflammatory signals in the pathogenesis of tubulointerstitial kidney disease due to UMOD mutations
title_full	Early involvement of cellular stress and inflammatory signals in the pathogenesis of tubulointerstitial kidney disease due to UMOD mutations
title_fullStr	Early involvement of cellular stress and inflammatory signals in the pathogenesis of tubulointerstitial kidney disease due to UMOD mutations
title_full_unstemmed	Early involvement of cellular stress and inflammatory signals in the pathogenesis of tubulointerstitial kidney disease due to UMOD mutations
title_sort	early involvement of cellular stress and inflammatory signals in the pathogenesis of tubulointerstitial kidney disease due to umod mutations
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/dad07a09c2784d458c8b05679b0804dd
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Early involvement of cellular stress and inflammatory signals in the pathogenesis of tubulointerstitial kidney disease due to UMOD mutations

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