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HIV-1 gp160 envelope protein modulates proliferation and apoptosis in mesangial cells
P C Singhal1, P Sharma, K Reddy
1Department of Medicine, Long Island Jewish Medical Center, and Long Island Campus for Albert Einstein College of Medicine, New York, NY 11040, USA.
Abstract:
Mesangial cell (MC) hyperplasia and accumulation of extracellular matrix are the predominant features of HIV-associated nephropathy (HIVAN). Since mice transgenic for HIV-1 genes show renal lesions mimicking HIVAN, we studied the effect of HIV-1 gp160 protein on cultured murine MC (MMC) proliferation and apoptosis. HIV-1 gp160 protein stimulated (p < 0.001) MMC proliferation when compared with control MMCs. This effect of gp160 protein peaked at a concentration of 0.01 microg/ml. MMCs treated with a higher concentration of gp160 protein (0.1 microg/ml) or for a prolonged period of time (72 h) showed apoptosis rather than cell proliferation. These studies were further confirmed by DNA fragmentation and end labeling assays. gp160 also enhanced apoptosis in human MCs. Tumor necrosis factor (TNF)-alpha enhanced (p < 0.001) MMC apoptosis, and anti-TNF-alpha antibodies inhibited gp160-induced MMC apoptosis. In addition, gp160 protein attenuated MMC expression of Bcl-2 mRNA expression. These results suggest that gp160-induced apoptosis may be affected in part by the release of TNF-alpha and associated with attenuated mRNA expression of Bcl-2 by MMCs.
Insights
HIV-1 gp160 protein promotes mesangial cell (MC) proliferation at low doses but induces apoptosis at higher concentrations or prolonged exposure. This gp160-induced apoptosis is mediated partly by tumor necrosis factor-alpha and reduced Bcl-2 mRNA expression.
Area of Science:
- Nephrology
- Virology
- Cell Biology
Background:
- HIV-associated nephropathy (HIVAN) is characterized by mesangial cell (MC) hyperplasia and extracellular matrix accumulation.
- Transgenic mice with HIV-1 genes develop renal lesions similar to HIVAN, suggesting a role for viral proteins.
Purpose of the Study:
- To investigate the effects of HIV-1 gp160 protein on cultured murine mesangial cell (MMC) proliferation and apoptosis.
- To explore the mechanisms underlying gp160-induced apoptosis, including the role of TNF-alpha and Bcl-2 expression.
Main Methods:
- Cultured murine mesangial cells (MMCs) were treated with varying concentrations and durations of HIV-1 gp160 protein.
- Cell proliferation was assessed, and apoptosis was confirmed using DNA fragmentation and end labeling assays.
- The role of TNF-alpha was investigated using anti-TNF-alpha antibodies, and Bcl-2 mRNA expression was measured.
Main Results:
- HIV-1 gp160 protein significantly stimulated MMC proliferation at low concentrations (0.01 microg/ml).
- Higher concentrations (0.1 microg/ml) or prolonged exposure (72 h) of gp160 induced MMC apoptosis, also observed in human MCs.
- gp160-induced apoptosis was partially inhibited by anti-TNF-alpha antibodies and associated with decreased Bcl-2 mRNA expression.
Conclusions:
- HIV-1 gp160 protein has a dual effect on mesangial cells, promoting proliferation at low doses and inducing apoptosis at higher doses or with prolonged exposure.
- gp160-induced apoptosis in MMCs is partly mediated by TNF-alpha and linked to reduced Bcl-2 mRNA expression.
- These findings provide insights into the pathogenesis of HIVAN and the cellular mechanisms involved.