title: Pathogenic pathways are activated in each major cell type of the glomerulus in the Cd2ap mutant mouse model of focal segmental glomerulosclerosis.
abstract: BACKGROUND
  Mutations in several genes expressed in podocytes, including Cd2ap, have been associated with focal segmental glomerulosclerosis in humans. Mutant mouse models provide an opportunity to better understand the molecular pathology that drives these diseases.
  
  
  METHODS
  In this report we use a battery of transgenic-GFP mice to facilitate the purification of all three major cell types of the glomerulus from Cd2ap mutant mice. Both microarrays and RNA-seq were used to characterize the gene expression profiles of the podocytes, mesangial cells and endothelial cells, providing a global dual platform cross-validating dataset.
  
  
  RESULTS
  The mesangial cells showed increased expression of profibrotic factors, including thrombospondin, Tgfb2 and Tgfb3, as well as the angiogenesis factor Vegf. They also showed upregulation of protective genes, including Aldh1a2, involved in retinoic acid synthesis and Decorin, a Tgfb antagonist. Of interest, the mesangial cells also showed significant expression of Wt1, which has generally been considered podocyte specific. The Cd2ap mutant podocytes showed upregulation of proteases as well as genes involved in muscle and vasculature development and showed a very strong gene expression signature indicating programmed cell death. Endothelial cells showed increased expression of the leukocyte adhesion associated factors Vcam1 and Sele, as well as Midkine (promoting angiogenesis), endothelin and many genes responsive to cytokines and interferons.
  
  
  CONCLUSIONS
  This study provides a comprehensive analysis of the changing properties of the three cell types of the glomerulus in Cd2ap mutants, identifying activated and repressed pathways and responsible genes, thereby delivering a deeper molecular understanding of this genetic disease.
authors.affiliation: Cincinnati Children's Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45229, USA. Eric.Brunskill@cchmc.org.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Brunskill
authors.affiliation: Cincinnati Children's Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45229, USA. Steve.Potter@cchmc.org.
authors.forename: S Steven
authors.initials: SS
authors.lastname: Potter
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D003598:Cytoskeletal Proteins / Q000235:genetics*; D058575:Decorin / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D016232:Endothelins / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007678:Kidney Glomerulus / Q000166:cytology / Q000378:metabolism; D050527:Mesangial Cells / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D000078792:Midkine; D009154:Mutation; D050199:Podocytes / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D050697:Retinal Dehydrogenase; D019699:Thrombospondins / Q000235:genetics / Q000378:metabolism; D053781:Transforming Growth Factor beta2 / Q000235:genetics / Q000378:metabolism; D053782:Transforming Growth Factor beta3 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D025721:WT1 Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C114545:CD2-associated protein; D003598:Cytoskeletal Proteins; C546879:Dcn protein, mouse; D058575:Decorin; D019040:E-Selectin; D016232:Endothelins; D036341:Intercellular Signaling Peptides and Proteins; C582105:Mdk protein, mouse; D012097:Repressor Proteins; C509042:Tgfb2 protein, mouse; C509045:Tgfb3 protein, mouse; D019699:Thrombospondins; D053781:Transforming Growth Factor beta2; D053782:Transforming Growth Factor beta3; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D025721:WT1 Proteins; C000602896:WT1 protein, mouse; C467480:vascular endothelial growth factor A, mouse; D000078792:Midkine; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C512722:Aldh1a2 protein, mouse; D050697:Retinal Dehydrogenase