title: Genetic Background is a Key Determinant of Glomerular Extracellular Matrix Composition and Organization.
abstract: Glomerular disease often features altered histologic patterns of extracellular matrix (ECM). Despite this, the potential complexities of the glomerular ECM in both health and disease are poorly understood. To explore whether genetic background and sex determine glomerular ECM composition, we investigated two mouse strains, FVB and B6, using RNA microarrays of isolated glomeruli combined with proteomic glomerular ECM analyses. These studies, undertaken in healthy young adult animals, revealed unique strain- and sex-dependent glomerular ECM signatures, which correlated with variations in levels of albuminuria and known predisposition to progressive nephropathy. Among the variation, we observed changes in netrin 4, fibroblast growth factor 2, tenascin C, collagen 1, meprin 1-α, and meprin 1-β. Differences in protein abundance were validated by quantitative immunohistochemistry and Western blot analysis, and the collective differences were not explained by mutations in known ECM or glomerular disease genes. Within the distinct signatures, we discovered a core set of structural ECM proteins that form multiple protein-protein interactions and are conserved from mouse to man. Furthermore, we found striking ultrastructural changes in glomerular basement membranes in FVB mice. Pathway analysis of merged transcriptomic and proteomic datasets identified potential ECM regulatory pathways involving inhibition of matrix metalloproteases, liver X receptor/retinoid X receptor, nuclear factor erythroid 2-related factor 2, notch, and cyclin-dependent kinase 5. These pathways may therefore alter ECM and confer susceptibility to disease.
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom; Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom;
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Randles
authors.affiliation: Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom;
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Woolf
authors.affiliation: Developmental Biology and Cancer Program, Institute of Child Health, University College London, London, United Kingdom;
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Huang
authors.affiliation: Edinburgh Cancer Research United Kingdom Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom; and.
authors.forename: Adam
authors.initials: A
authors.lastname: Byron
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom;
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Humphries
authors.affiliation: Developmental Biology and Cancer Program, Institute of Child Health, University College London, London, United Kingdom;
authors.forename: Karen L
authors.initials: KL
authors.lastname: Price
authors.affiliation: Developmental Biology and Cancer Program, Institute of Child Health, University College London, London, United Kingdom;
authors.forename: Maria
authors.initials: M
authors.lastname: Kolatsi-Joannou
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom;
authors.forename: Sophie
authors.initials: S
authors.lastname: Collinson
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom; Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom;
authors.forename: Thomas
authors.initials: T
authors.lastname: Denny
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom;
authors.forename: David
authors.initials: D
authors.lastname: Knight
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom;
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Mironov
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom;
authors.forename: Toby
authors.initials: T
authors.lastname: Starborg
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine.
authors.forename: Ron
authors.initials: R
authors.lastname: Korstanje
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom;
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Humphries
authors.affiliation: Developmental Biology and Cancer Program, Institute of Child Health, University College London, London, United Kingdom;
authors.forename: David A
authors.initials: DA
authors.lastname: Long
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom; Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom; Rachel.Lennon@manchester.ac.uk.
authors.forename: Rachel
authors.initials: R
authors.lastname: Lennon
mesh_terms: D000419:Albuminuria / Q000235:genetics / Q000378:metabolism; D000818:Animals; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D005109:Extracellular Matrix / Q000235:genetics* / Q000378:metabolism* / Q000648:ultrastructure; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D050533:Glomerular Basement Membrane / Q000648:ultrastructure; D007674:Kidney Diseases / Q000235:genetics* / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism*; D000071518:Liver X Receptors; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D000075385:Netrins; D020411:Oligonucleotide Array Sequence Analysis; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D012313:RNA / Q000032:analysis; D012737:Sex Factors; D015398:Signal Transduction; D019063:Tenascin / Q000235:genetics / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D000071518:Liver X Receptors; D051267:NF-E2-Related Factor 2; D009414:Nerve Growth Factors; D000075385:Netrins; C495636:Nfe2l2 protein, mouse; C416214:Ntn4 protein, mouse; D057093:Orphan Nuclear Receptors; D019063:Tenascin; D016222:Fibroblast Growth Factor 2; D012313:RNA; D051360:Cyclin-Dependent Kinase 5; D020782:Matrix Metalloproteinases; D008666:Metalloendopeptidases; C053833:meprin A
keywords: albuminuria; cell-matrix-interactions; extracellular matrix