title: Kidneys with heavy proteinuria show fibrosis, inflammation, and oxidative stress, but no tubular phenotypic change.
abstract: BACKGROUND
  Sustained proteinuria is a major factor leading to kidney fibrosis and end-stage renal failure. Tubular epithelial cells are believed to play a crucial role in this process by producing mediators leading to fibrosis and inflammation. Congenital nephrotic syndrome of the Finnish type (NPHS1) is a genetic disease caused by mutations in a podocyte protein nephrin, which leads to constant heavy proteinuria from birth. In this work we studied the tubulointerstitial changes that occur in NPHS1 kidneys during infancy.
  
  
  METHODS
  The pathologic lesions and expression of profibrotic and proinflammatory factors in nephrectomized NPHS1 kidneys were studied by immunohistochemistry, Western blotting, and cytokine antibody array. Oxidative stress in kidneys was assessed by measurement of gluthatione redox state.
  
  
  RESULTS
  The results indicated that (1) severe tubulointerstitial lesions developed in NPHS1 kidneys during infancy; (2) tubular epithelial cells did not show transition into myofibroblasts as studied by the expression of vimentin, alpha-smooth muscle actin (alpha-SMA), collagen, and matrix metalloproteinases 2 and 9 (MMP-2 and -9); (3) the most abundant chemokines in NPHS1 tissue were neutrophil activating protein-2 (NAP-2), macrophage inhibiting factor (MIF), and monocyte chemoattractant protein-1 (MCP-1); (4) monocyte/macrophage cells expressing CD14 antigen were the major inflammatory cells invading the interstitium; (5) the arteries and arterioles showed intimal hypertrophy, but the microvasculature in NPHS1 kidneys remained quite normal; and (6) excessive oxidative stress was evident in NPHS1 kidneys.
  
  
  CONCLUSIONS
  Heavy proteinuria in NPHS1 kidneys was associated with interstitial fibrosis, inflammation, and oxidative stress. The tubular epithelial cells, however, were resistant to proteinuria and did not show epithelial-mesenchymal transition.
authors.affiliation: Hospital for Children and Adolescents and Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Arvi-Matti
authors.initials: AM
authors.lastname: Kuusniemi
authors.forename: Risto
authors.initials: R
authors.lastname: Lapatto
authors.forename: Christer
authors.initials: C
authors.lastname: Holmberg
authors.forename: Riitta
authors.initials: R
authors.lastname: Karikoski
authors.forename: Juhani
authors.initials: J
authors.lastname: Rapola
authors.forename: Hannu
authors.initials: H
authors.lastname: Jalanko
mesh_terms: D002196:Capillaries / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018925:Chemokines / Q000378:metabolism; D002675:Child, Preschool; D016207:Cytokines / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D007223:Infant; D007684:Kidney Tubules / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D009393:Nephritis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D009404:Nephrotic Syndrome / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress; D010641:Phenotype; D011507:Proteinuria / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology*
chemical_list: D018925:Chemokines; D016207:Cytokines; D008565:Membrane Proteins; C113267:nephrin