Expression of HIV-1 genes in podocytes alone can lead to the full spectrum of HIV-1-associated nephropathy

Jianyong Zhong, Yiqin Zuo, Ji Ma, Agnes B. Fogo, Paul Jolicoeur, Iekuni Ichikawa, Taiji Matsusaka

Research output: Contribution to journalArticlepeer-review

107 Scopus citations

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. Conclusion. 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.

Original languageEnglish (US)
Pages (from-to)1048-1060
Number of pages13
JournalKidney international
Volume68
Issue number3
DOIs
StatePublished - Sep 2005
Externally publishedYes

Keywords

  • HIV-1-associated nephropathy
  • Podocyte damage
  • Proteinuria

ASJC Scopus subject areas

  • Nephrology

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