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Alport syndrome: Proteomic analysis identifies early molecular pathway alterations in Col4a3 knock out mice

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Title: Alport syndrome: Proteomic analysis identifies early molecular pathway alterations in Col4a3 knock out mice
Authors: Nicolaou, O
Kousios, A
Sokratous, K
Potamiti, L
Koniali, L
Neophytou, G
Papacharalampous, R
Zanti, M
Ioannou, K
Hadjisavvas, A
Stingl, C
Luider, TM
Kyriacou, K
Item Type: Journal Article
Abstract: AIM: Alport syndrome (AS) is the second most common hereditary kidney disease caused by mutations in collagen IV genes. Patients present with microhaematuria that progressively leads to proteinuria and end stage renal disease. Currently, no specific treatment exists for AS. Using mass spectrometry based proteomics, we aimed to detect early alterations in molecular pathways implicated in AS before the stage of overt proteinuria, which could be amenable to therapeutic intervention. METHODS: Kidneys were harvested from male Col4a3-/- knock out and sex and age-matched Col4a3+/+ wild-type mice at 4 weeks of age. Purified peptides were separated by liquid chromatography and analysed by high resolution mass spectrometry. The Cytoscape bioinformatics tool was used for function enrichment and pathway analysis. PPARα expression levels were evaluated by immunofluorescence and immunoblotting. RESULTS: Proteomic analysis identified 415 significantly differentially expressed proteins, which were mainly involved in metabolic and cellular processes, the extracellular matrix, binding and catalytic activity. Pathway enrichment analysis revealed among others, downregulation of the proteasome and PPAR pathways. PPARα protein expression levels were observed to be downregulated in Alport mice, supporting further the results of the discovery proteomics. CONCLUSION: This study provides additional evidence that alterations in proteins which participate in cellular metabolism and mitochondrial homeostasis in kidney cells are early events in the development of chronic kidney disease in AS. Of note is the dysregulation of the PPAR pathway, which is amenable to therapeutic intervention and provides a new potential target for therapy in AS.
Issue Date: 2-Aug-2020
Date of Acceptance: 26-Jul-2020
URI: http://hdl.handle.net/10044/1/81916
DOI: 10.1111/nep.13764
ISSN: 1320-5358
Publisher: Wiley
Journal / Book Title: Nephrology
Copyright Statement: © 2020 The Authors. Nephrology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Nephrology. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
Keywords: Alport syndrome
Col4a3 knockout mice
PPARα
mass spectrometry
proteomics
Alport syndrome
Col4a3 knockout mice
PPARα
mass spectrometry
proteomics
Urology & Nephrology
1103 Clinical Sciences
Publication Status: Published online
Conference Place: Australia
Open Access location: https://onlinelibrary.wiley.com/doi/abs/10.1111/nep.13764
Online Publication Date: 2020-08-02
Appears in Collections:Department of Immunology and Inflammation



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