HIV-1 gp160 Protein Modulates Proximal Tubular Cell Proliferation and Matrix Synthesis

Abstract

Cystic dilatation and tubular cell proliferation are unique features of HIV-associated nephropathy. We studied the effect of HIV-1 envelope gp160 protein on human renal proximal tubular epithelial cells (RPTEC) and opossum kidney (OK) cells. gp160 protein enhanced (p < 0.01) the proliferation of RPTEC when compared to control cells (control 9.0 ± 1.4 vs. gp160 protein 19.3 ± 2.0 × 10⁴ cells/ml). Similarly, gp160 protein stimulated (p < 0.001) the proliferation of OK cells. This effect of gp160 was dose dependent. Both anti-tumor necrosis factor alpha and anti-transforming growth factor beta antibodies inhibited the gp160-induced OK cell proliferation. However, the inhibitory effect of anti-tumor necrosis factor alpha antibodies was more pronounced on RPTEC when compared to the inhibitory effect of anti-transforming growth factor beta antibodies. Other HIV-1 proteins (TAT and Gag4) did not affect the growth of tubular cells. gp160 protein attenuated (p < 0.001) the synthesis of collagen type I (control 883.2 ± 42.3 vs. gpl60 579.6 ± 57.6 ng/well), but increased the production of proteoglycan (control 5,832.3 ± 426 vs. gp160 9,018.0 ± 471.1 ng/well) by RPTEC. gp160 also attenuated the synthesis of collagen type I by OK cells. We hypothesize that gp160 protein-induced altered basement membrane composition and associated cell proliferation may be contributing to tubulointerstitial lesions of HIV-associated nephropathy.

Exosome-associated release, uptake, and neurotoxicity of HIV-1 Tat protein

“…These include activated production and expression of growth factors (Gibellini et al 1994) and cytokines (Cupp et al 1993; Nabell et al 1994; Sastry et al 1990) and of cytokine receptors (Ganju et al 1998; Pocsik et al 1992; Puri and Aggarwal 1992), stimulation of cell proliferation and migration (Albini et al 1996b; Singhal et al 1995) and protease production, chemoattractant activity of monocytes (Albini et al 1998c; Huang et al 1998), and angiogenic activity (Albini et al 1994, 1995, 1996a; Barbanti-Brodano et al 1994; Corallini et al 1996). Extracellular Tat also transforms and immortalizes keratinocytes in cultures (Schuurman et al 1993).…”

Tubular Cell HIV-1 gp120 Expression Induces Caspase 8 Activation and Apoptosis

“…[28][29][30][31][32] Studies suggest that HIV-1 glycoprotein causes apoptosis in human proximal renal tubular HK-2 cells at higher concentrations. [33][34][35] Lower concentrations of gp120 have also been reported to induce NFkB activation. [36,37] Ross et al reported that NFkB upregulates Fas receptor and ligand proteins on epithelium in diseased glomerular and tubulointerstitial compartments in human HIVAN specimens.…”

“…Double staining by these two agents provides the percentage of live, apoptotic, and necrotic cells. [22] HK-2 cells were grown in keratinocyte-SFM media and transduced with the virus expressing gp120 and vector alone as described above. Analysis for apoptosis was performed after every 12 hrs of incubation period for three days.…”

“…Several studies have tried to dissect out the role of individual HIV-1 genes in glomerular epithelial cells, but no such data are available on tubular epithelial cells. In previous studies, HIV-1 gp120 protein has been shown to induce both proliferation and apoptosis in renal cells [20][21][22][23][24][25] ; however, in the role of HIV-1, gene expression was not studied.…”

Controversies in the pathogenesis of HIV-associated renal diseases

“…This hypothesis is supported by several in vitro studies evaluating the effects of exogenous viral proteins on renal cell behavior. The direct application of purified viral proteins such as the precursor envelope polyprotein gp160 and its major surface fragment gp12071–74 or Tat56,57 to renal cell cultures can induce a variety of responses relevant to HIVAN cell phenotypes. Such responses include activation of intracellular signaling cascades, loss of key differentiation proteins, proliferation, and apoptosis.…”