p300 Modulates HIV-1 gp120-Induced Apoptosis in Human Proximal Tubular Cells: Associated with Alteration of TGF-β and Smad Signaling

Abstract

p300 is a key protein, which determines acceleration or deceleration of signal transduction. Recently, renal proximal tubular cells have not only been found to be a harboring site for HIV-1 but have also been shown to undergo apoptosis in response to HIV-1 exposure. Both HIV-1 and its envelop glycoprotein, i.e. gp120, triggered tubular cell apoptosis in the same magnitude. In the present study, we evaluated the role of p300 in gp120-induced tubular cell apoptosis and associated downstream signaling. We have demonstrated that by transient transfection assays, p300 significantly increases susceptibility of human proximal renal tubular HK-2 cells to apoptosis triggered by HIV-1 gp120. A mutant p300, missing the E1A/TFIIB binding site, fails to produce such sensitization potential. Smad7 and an anti-TGF-β antibody rescue the p300 sensitization. Furthermore, p300 and HIV-1 gp120 synergistically increase TGF-β, ATF-2 and activating protein-1 (AP-1) expression. In addition, HIV-1 gp120 results in phosphorylation of Smad2 and decreases c-Jun. These findings suggest that p300 acts as a potent transcriptional cofactor in HIV-1 gp120-induced apoptosis via TGF-β and Smad signaling.

HIV-1 stimulates nuclear entry of amyloid beta via dynamin dependent EEA1 and TGF-β/Smad signaling

“…Exposure to HIV-1 and/or Aβ increased pSmad2 levels in the nuclear fractions, without affecting the total Smad2 levels in the cytoplasm. The mechanisms of these effects are not fully understood; however, HIV-1 gp120 [36] can signal via transforming growth factor-β1 (TGF-β), providing an activation pathway for Smad2 stimulation. Indeed, Smad is typically activated by stimulation of the TGF-β family receptor complex, which compromises the activin-like kinase 5 (ALK5)/TGF-β type I receptor (TβRI) and the TGF-β type II receptor (TβRII) subunits.…”

HIV-induced kidney cell injury: role of ROS-induced downregulated vitamin D receptor

“…HIV has been reported to induce the apoptotic phenotype in tubular cells (26,42,45). Increasing evidence supports that oxidative stress is involved in the induction of HIVinduced kidney cell apoptosis (22,42).…”

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

“…[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. They also reported Fas mediated apoptosis in renal cells.…”

“…[47] HIV-1 has been reported to enhance tubular cell apoptosis. [33,37,48] Bruggeman et al evaluated the importance of HIV-1 transgene in the development of HIVAN. They carried out transplantation of kidneys between normal and HIV-transgenic mice.…”