RNA-seq analysis of gene expression profiles in isolated stria vascularis from wild-type and Alport mice reveals key pathways underling Alport strial pathogenesis

Previous work demonstrates that the hearing loss in Alport mice is caused by defects in the stria vascularis. As the animals age, progressive thickening of strial capillary basement membranes (SCBMs) occurs associated with elevated levels of extracellular matrix expression and hypoxia-related gene a...

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Published in:	PloS one Vol. 15; no. 8; p. e0237907
Main Authors:	Dufek, Brianna, Meehan, Daniel T, Delimont, Duane, Wilhelm, Kevin, Samuelson, Gina, Coenen, Ross, Madison, Jacob, Doyle, Edward, Smyth, Brendan, Phillips, Grady, Gratton, Michael Anne, Cosgrove, Dominic
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 21-08-2020 Public Library of Science (PLoS)
Subjects:	Animals Auditory defects Autoantigens - genetics Autoantigens - metabolism Basement Membrane - metabolism Basement membranes Bioinformatics Biology and life sciences Biosynthesis Calcium Calcium signalling Chemokine receptors Chemokines - genetics Chemokines - metabolism Clinical trials Cochlea Collagen Collagen (type IV) Collagen Type IV - genetics Collagen Type IV - metabolism Cytokines Cytokines - genetics Cytokines - metabolism Data points Degradation Development and progression Disease Models, Animal Down-Regulation Extracellular matrix Extracellular Matrix - metabolism Female Gene expression Gene Expression Regulation - genetics Genes Genetic aspects Genetic research Glucose Glucose - genetics Glucose - metabolism Glutamic acid receptors Health aspects Hearing Hearing loss Hearing Loss, Noise-Induced - genetics Hearing Loss, Noise-Induced - metabolism Hereditary nephritis Histidine Homeostasis Hospitals Hypoxia Inflammation Inflammation - genetics Inflammation - metabolism Inflammation - pathology Laboratory animals Ligaments Male Medical research Medicine Medicine and Health Sciences Membranes Metabolic pathways Metabolism Mice Modulation Mutation NAD Nephritis, Hereditary - genetics Nephritis, Hereditary - metabolism Nephritis, Hereditary - pathology Noise Otolaryngology Pathogenesis Permeability Receptors Ribonucleic acid RNA RNA sequencing RNA-Seq Signal transduction Signal Transduction - genetics Signaling Stria vascularis Stria Vascularis - metabolism Stria Vascularis - pathology Thickening Transcription factors Transcription Factors - genetics Transcription Factors - metabolism Transcriptome - genetics Up-Regulation United States United States > US
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Summary:	Previous work demonstrates that the hearing loss in Alport mice is caused by defects in the stria vascularis. As the animals age, progressive thickening of strial capillary basement membranes (SCBMs) occurs associated with elevated levels of extracellular matrix expression and hypoxia-related gene and protein expression. These conditions render the animals susceptible to noise-induced hearing loss. In an effort to develop a more comprehensive understanding of how the underlying mutation in the COL4A3 gene influences homeostasis in the stria vascularis, we performed vascular permeability studies combined with RNA-seq analysis using isolated stria vascularis from 7-week old wild-type and Alport mice on the 129 Sv background. Alport SCBMs were found to be less permeable than wild-type littermates. RNA-seq and bioinformatics analysis revealed 68 genes were induced and 61 genes suppressed in the stria from Alport mice relative to wild-type using a cut-off of 2-fold. These included pathways involving transcription factors associated with the regulation of pro-inflammatory responses as well as cytokines, chemokines, and chemokine receptors that are up- or down-regulated. Canonical pathways included modulation of genes associated with glucose and glucose-1-PO4 degradation, NAD biosynthesis, histidine degradation, calcium signaling, and glutamate receptor signaling (among others). In all, the data point to the Alport stria being in an inflammatory state with disruption in numerous metabolic pathways indicative of metabolic stress, a likely cause for the susceptibility of Alport mice to noise-induced hearing loss under conditions that do not cause permanent hearing loss in age/strain-matched wild-type mice. The work lays the foundation for studies aimed at understanding the nature of strial pathology in Alport mice. The modulation of these genes under conditions of therapeutic intervention may provide important pre-clinical data to justify trials in humans afflicted with the disease.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Competing Interests: The authors have declared that no competing interests exist.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0237907