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Nephropathy in human immunodeficiency virus-1 transgenic mice is due to renal transgene expression.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 1997 Jul 01; Vol. 100 (1), pp. 84-92. - Publication Year :
- 1997
-
Abstract
- HIV-associated nephropathy (HIVAN) is a progressive glomerular and tubular disease that is increasingly common in AIDS patients and one of the leading causes of end stage renal disease in African Americans. A major unresolved issue in the pathogenesis of HIVAN is whether the kidney disease is due to renal cell infection or a "bystander" phenomenon mediated by systemically dysregulated cytokines. To address this issue, we have used two different experimental approaches and an HIV-1 transgenic mouse line that develops a progressive renal disease histologically similar to HIVAN in humans. In the murine model, kidney tissue expresses the transgene and in heterozygous adults, renal disease develops shortly thereafter. We demonstrate by terminal deoxynucleotide transferase-mediated dUTP-biotin nick-end labeling assay that similar to the disease in humans, apoptosis of renal tubular epithelial cells is a component of the molecular pathogenesis. To determine whether apoptosis is due to transgene expression or environmental factors, we treated fetal kidney explants (normal and transgenic) with UV light to induce transgene expression. Apoptosis occurred in transgenic but not normal littermates after stimulation of transgene expression. To confirm a direct effect of HIV expression on the production of HIVAN, we transplanted kidneys between normal and transgenic mice. HIVAN developed in transgenic kidneys transplanted into nontransgenic littermates. Normal kidneys remained disease free when transplanted into transgenic littermates. Thus, the renal disease in the murine model is intrinsic to the kidney. Using two different experimental approaches, we demonstrate a direct effect of transgene expression on the development of HIVAN in the mouse. These studies suggest that in humans, a direct effect of HIV-1 expression is likely the essential cause of HIVAN, rather than an indirect effect of cytokine dysregulation.
- Subjects :
- AIDS-Associated Nephropathy epidemiology
AIDS-Associated Nephropathy transmission
Black or African American
Aging
Animals
Apoptosis
Cell Nucleus pathology
Cell Nucleus ultrastructure
Chromatin pathology
Chromatin ultrastructure
Gene Expression Regulation, Viral radiation effects
HIV-1 isolation & purification
Humans
Kidney virology
Kidney Transplantation pathology
Kidney Tubules pathology
Kidney Tubules radiation effects
Kidney Tubules virology
Mice
Mice, Transgenic
Ultraviolet Rays
United States epidemiology
AIDS-Associated Nephropathy pathology
HIV-1 genetics
Kidney pathology
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9738
- Volume :
- 100
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 9202060
- Full Text :
- https://doi.org/10.1172/JCI119525