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

Zhong J, Zuo Y, Ma J, Fogo AB, Jolicoeur P, Ichikawa I, Matsusaka T
Kidney Int. 2005 68 (3): 1048-60

PMID: 16105035 · DOI:10.1111/j.1523-1755.2005.00497.x

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.

MeSH Terms (15)

AIDS-Associated Nephropathy Animals Female Gene Expression Regulation, Viral Genetic Predisposition to Disease HIV-1 Male Membrane Proteins Mice Mice, Inbred C57BL Mice, Transgenic Nephrotic Syndrome Podocytes Promoter Regions, Genetic Transgenes

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