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

Autor: Kyriacos Kyriacou, Andreas Kousios, Kyriakos Ioannou, Louiza Potamiti, Theo M. Luider, Orthodoxia Nicolaou, Christoph Stingl, Revekka Papacharalampous, Andreas Hadjisavvas, George Neophytou, Lola Koniali, Kleitos Sokratous, Maria Zanti
Přispěvatelé: Neurology
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Collagen Type IV
Male
Proteomics
RENAL-FAILURE
030232 urology & nephrology
ENERGY-METABOLISM
Peroxisome proliferator-activated receptor
Nephritis
Hereditary
030204 cardiovascular system & hematology
Col4a3 knockout mice
PPARα
Autoantigens
End stage renal disease
03 medical and health sciences
Mice
0302 clinical medicine
Downregulation and upregulation
PPAR-ALPHA
medicine
FIBROSIS
Animals
PPAR alpha
Alport syndrome
mass spectrometry
chemistry.chemical_classification
Mice
Knockout
Kidney
Science & Technology
business.industry
Col4a3knockout mice
1103 Clinical Sciences
General Medicine
PPAR Pathway
Original Articles
Urology & Nephrology
medicine.disease
RECEPTORS
Disease Models
Animal
medicine.anatomical_structure
Basic Research
chemistry
Nephrology
Cancer research
Original Article
business
Life Sciences & Biomedicine
Kidney disease
Zdroj: Nephrology (Carlton, Vic.)
Nephrology, 25(12), 937-949. Wiley-Blackwell Publishing Ltd
ISSN: 1440-1797
1320-5358
Popis: 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.
SUMMARY AT A GLANCE Alterations in proteins which participate in cellular metabolism and mitochondrial homeostasis in kidney cells, are early events in the development of CKD in Alport syndrome. In addition, pathway enrichment analysis revealed among others, dysregulation of the proteasome, protein digestion and absorption pathways as well as PPAR pathway in AS compared to control mice. Targeting the PPAR pathway could be a potential therapeutic approach in AS.
Databáze: OpenAIRE
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