Dataset Information

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

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. PPAR? 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. PPAR? 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.

SUBMITTER: Nicolaou O

PROVIDER: S-EPMC7754404 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Publications

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

Nicolaou Orthodoxia O Kousios Andreas A Sokratous Kleitos K Potamiti Louiza L Koniali Lola L Neophytou George G Papacharalampous Revekka R Zanti Maria M Ioannou Kyriakos K Hadjisavvas Andreas A Stingl Christoph C Luider Theo M TM Kyriacou Kyriacos K

Nephrology (Carlton, Vic.) 20200820 12

<h4>Aim</h4>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.<h4>Metho ...[more]

PMID: 32743880

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Project description:IntroductionThe chromosome 22q11.2 deletion syndrome (22q11.2DS) is characterized by a well-defined microdeletion and is associated with a wide range of brain-related phenotypes including schizophrenia spectrum disorders (SCZ), autism spectrum disorders (ASD), anxiety disorders and attention deficit disorders (ADHD). The typically deleted region in 22q11.2DS contains multiple genes which haploinsufficiency has the potential of altering the protein and the metabolic profiles.ObjectivesAlteration in metabolic processes and downstream protein pathways during the early brain development may help to explain the increased prevalence of the observed neurodevelopmental phenotypes in 22q11.2DS. However, relatively little is known about the correlation of dysregulated protein/metabolite expression and neurobehavioral impairments in individuals who developed them over time.MethodsIn this study, we performed untargeted metabolic and proteomic analysis in plasma samples derived from 30 subjects including 16 participants with 22q11.2DS and 14 healthy controls (TD) enrolled in a longitudinal study, aiming to identify a metabolic and protein signature informing about the underlying mechanisms involved in disease development and progression. The metabolic and proteomic profiles were also compared between the participants with 22q11.2DS with and without various comorbidities, such as medical involvement, psychiatric conditions, and autism spectrum disorder (ASD) to detect potential changes among multiple specimens, collected overtime, with the aim to understand the basic underlying mechanisms involved in disease development and progression.ResultsWe observed a large number of statistically significant differences in metabolites between the two groups. Among them, the levels of taurine and arachidonic acid were significantly lower in 22q11.2DS compared to the TD group. In addition, we identified 16 proteins that showed significant changes in expression levels (adjusted P < 0.05) in 22q11.2DS as compared to TD, including those involved in 70 pathways such as gene expression, the PI3K-Akt signaling pathway and the complement system. Within participants with 22q11.2DS, no significant changes in those with and without medical or psychiatric conditions were observed.ConclusionTo our knowledge, this is the first report on plasma metabolic and proteomic profiling and on the identification of unique biomarkers in 22q11.2DS. These findings may suggest the potential role of the identified metabolites and proteins as biomarkers for the onset of comorbid conditions in 22q11.2DS. Ultimately, the altered protein pathways in 22q11.2DS may provide insights of the biological mechanisms underlying the neurodevelopmental phenotype and may provide missing molecular outcome measures in future clinical trials to assess early-diagnosis treatment and the efficacy of response to targeted treatment.

Dataset Information

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

Aim

Methods

Results

Conclusion

Publications

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

Similar Datasets

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