title: Expression of HIV-1 genes in podocytes alone can lead to the full spectrum of HIV-1-associated nephropathy.
abstract: BACKGROUND
  Human immunodeficiency virus (HIV)-1-associated nephropathy (HIVAN) is characterized by collapsing focal and segmental glomerulosclerosis (FSGS) and microcystic tubular dilatation. HIV-1 infection is also associated with other forms of nephropathy, including mesangial hyperplasia. Since HIV-1 gene products are detected in podocytes and other renal cells, it remains uncertain whether podocyte-restricted HIV-1 gene expression can account for the full spectrum of renal lesions involving nonpodocytes.
  
  
  METHODS
  To define the role of podocyte-restricted HIV-1 gene expression in the progression of HIVAN, we generated transgenic mice that express nonstructural HIV-1 genes selectively in podocytes.
  
  
  RESULTS
  Four of the seven founder mice developed proteinuria and nephropathy. In a subsequently established transgenic line, reverse transcription-polymerase chain reaction (RT-PCR) analysis detected mRNAs for vif, vpr, nef, and spliced forms of tat and rev, but not vpu, in the kidney. In situ hybridization localized HIV-1 RNA to the podocyte. Transgenic mice on FVB/N genetic background exhibited cuboidal morphology of podocytes with reduced extension of primary and foot processes at 2 weeks of age. After 3 weeks of age, these mice developed massive and nonselective proteinuria with damage of podocytes and other glomerular cells and, after 4 weeks of age, collapsing FSGS and microcystic tubular dilatation. In marked contrast, transgenic mice with C57BL/6 genetic background showed either normal renal histology or only mild mesangial expansion without overt podocyte damage.
  
  
  CONCLUSIONS
  The present study demonstrates that podocyte-restricted expression of HIV-1 gene products is sufficient for the development of collapsing glomerulosclerosis in the setting of susceptible genetic background.
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37232-3584, USA.
authors.forename: Jianyong
authors.initials: J
authors.lastname: Zhong
authors.forename: Yiqin
authors.initials: Y
authors.lastname: Zuo
authors.forename: Ji
authors.initials: J
authors.lastname: Ma
authors.forename: Agnes B
authors.initials: AB
authors.lastname: Fogo
authors.forename: Paul
authors.initials: P
authors.lastname: Jolicoeur
authors.forename: Iekuni
authors.initials: I
authors.lastname: Ichikawa
authors.forename: Taiji
authors.initials: T
authors.lastname: Matsusaka
mesh_terms: D016263:AIDS-Associated Nephropathy / Q000235:genetics / Q000503:physiopathology* / Q000821:virology*; D000818:Animals; D005260:Female; D015967:Gene Expression Regulation, Viral; D020022:Genetic Predisposition to Disease; D015497:HIV-1 / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009404:Nephrotic Syndrome / Q000235:genetics / Q000503:physiopathology / Q000821:virology; D050199:Podocytes / Q000473:pathology / Q000502:physiology* / Q000821:virology*; D011401:Promoter Regions, Genetic; D019076:Transgenes / Q000235:genetics
chemical_list: D008565:Membrane Proteins; C113267:nephrin