4.7 Article

Genetic Background is a Key Determinant of Glomerular Extracellular Matrix Composition and Organization

Journal

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
Volume 26, Issue 12, Pages 3021-3034

Publisher

AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2014040419

Keywords

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Funding

  1. Wellcome Trust Intermediate Fellowship award [090006]
  2. Kids Kidney Research grant
  3. Kidney Research UK Senior Non-Clinical Fellowship [SF112008]
  4. Medical Research Council New Investigator Award [MR/J003638/1]
  5. Wellcome Trust [092015, 097820/Z/11/B]
  6. Biotechnology and Biological Sciences Research Council
  7. University of Manchester Strategic Fund
  8. MRC [MR/J003638/1] Funding Source: UKRI
  9. Diabetes UK [13/0004763] Funding Source: researchfish
  10. Kidney Research UK [RP52/2014, RP18/2011, RP38/2013, SF1/2008] Funding Source: researchfish
  11. Medical Research Council [MR/J003638/1] Funding Source: researchfish

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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 nnicroarrays 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-alpha, and meprin 1-beta. 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 nnetalloproteases, 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.

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