title: HIV-1 induces renal epithelial dedifferentiation in a transgenic model of HIV-associated nephropathy.
abstract: BACKGROUND
  Human immunodeficiency virus-associated nephropathy (HIVAN) is the most common cause of renal failure in HIV-1-seropositive patients. Recent studies using an HIV-1 transgenic mouse model have demonstrated that expression of HIV-1 in the kidney is required for the development of HIVAN. What has remained unclear, however, is the renal cell type responsible for pathogenesis and the essential pathological process.
  
  
  METHODS
  To address these issues, we used a transgenic murine model of HIVAN. We identified the cell types in kidney in which HIV transgene expression occurs using in situ hybridization. We evaluated evidence of proliferation by immunocytochemical analysis using an antibody to Ki-67 and cell type-specific markers, including WT-1, synaptopodin, Na+,K+-ATPase, adducin, and desmin. TUNEL assay was used to evaluate apoptosis.
  
  
  RESULTS
  We found that glomerular and tubular epithelial cells express the HIV-1 transgene early in the disease process when renal architecture is well preserved. Transgene expression is lost, however, in tubular epithelial cells when they lose their differentiated cuboidal phenotype. In glomerular epithelial cells, dedifferentiation occurs with reduced expression of WT-1 and synaptopodin, in association with activation of desmin expression. Tubular microcysts also form with mislocalization of Na+,K+-ATPase expression to the lateral and apical cellular membranes.
  
  
  CONCLUSIONS
  These studies support the hypothesis that the glomerular and renal epithelial cells are the primary targets of HIV-1 pathogenesis in the kidney. The essential pathologic process is dysregulation of the epithelial cell cycle with increased proliferation, apoptosis, cellular dedifferentiation, and altered cellular polarity.
authors.affiliation: Department of Pathology, Columbia Presbyterian Medical Center, Mount Sinai School of Medicine, NY 10029, USA.
authors.forename: L
authors.initials: L
authors.lastname: Barisoni
authors.forename: L A
authors.initials: LA
authors.lastname: Bruggeman
authors.forename: P
authors.initials: P
authors.lastname: Mundel
authors.forename: V D
authors.initials: VD
authors.lastname: D'Agati
authors.forename: P E
authors.initials: PE
authors.lastname: Klotman
mesh_terms: D016263:AIDS-Associated Nephropathy / Q000235:genetics* / Q000473:pathology*; D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015415:Biomarkers; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D016764:Cell Polarity / Q000502:physiology; D004268:DNA-Binding Proteins / Q000032:analysis; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D005333:Fetus / Q000737:chemistry / Q000201:enzymology / Q000473:pathology; D015497:HIV-1 / Q000235:genetics*; D020287:In Situ Nick-End Labeling; D019394:Ki-67 Antigen / Q000032:analysis; D007676:Kidney Failure, Chronic / Q000235:genetics / Q000473:pathology / Q000821:virology; D007678:Kidney Glomerulus / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000032:analysis; D000254:Sodium-Potassium-Exchanging ATPase / Q000032:analysis; D014157:Transcription Factors / Q000032:analysis; D019076:Transgenes / Q000502:physiology; D025721:WT1 Proteins
chemical_list: D015415:Biomarkers; D004268:DNA-Binding Proteins; D019394:Ki-67 Antigen; D008840:Microfilament Proteins; C503967:SYNPO protein, human; C503968:Synpo protein, mouse; D014157:Transcription Factors; D025721:WT1 Proteins; D000254:Sodium-Potassium-Exchanging ATPase