title: HIV gene expression deactivates redox-sensitive stress response program in mouse tubular cells both in vitro and in vivo.
abstract: Human immunodeficiency virus (HIV)-1 has been reported to cause tubular cell injury both in in vivo and in vitro studies. In the present study, we evaluated the role of oxidative stress in the induction of apoptosis in HIV gene expressing mouse tubular cells in in vivo (Tg26, a transgenic mouse model of HIV-associated nephropathy) and in vitro (tubular cells were transduced with pNL4-3: ΔG/P-GFP, VSV.G psueudo typed virus) studies. Although Tg26 mice showed enhanced tubular cell reactive oxygen species (ROS) generation and apoptosis, renal tissue did not display a robust antioxidant response in the form of enhanced free radical scavenger (MnSOD/catalase) expression. Tg26 mice not only showed enhanced tubular cell expression of phospho-p66ShcA but also displayed nuclear Foxo3a translocation to the cytoplasm. These findings indicated deactivation of tubular cell Foxo3A-dependent redox-sensitive stress response program (RSSRP) in Tg26 mice. In in vitro studies, NL4-3 (pNL4-3: ΔG/P-GFP, VSV.G pseudotyped virus)-transduced mouse proximal tubular cells (NL4-3/MPTEC) displayed enhanced phosphorylation of p66ShcA. NL4-3/MPTECs also displayed greater (P < 0.01) ROS generation when compared with empty vector-transduced tubular cells; however, both diminution of p66ShcA and N-acetyl cysteine attenuated NL4-3-induced tubular cell ROS generation as well as apoptosis. In addition, both antioxidants and free radical scavengers partially inhibited HIV-induced tubular cell apoptosis. NL4-3/MPTEC displayed deactivation of RSSRP in the form of enhanced phosphorylation of Foxo3A and attenuated expression of superoxide dismutase (SOD) and catalase. Since both SOD and catalase were able to provide protection against HIV-1-induced tubular cell apoptosis, it suggests that HIV-1-induced proapoptotic effect may be a consequence of the deactivated RSSRP.
authors: North Shore-LIJ Health System, Department of Medicine, Division of Kidney Diseases and Hypertension, New Hyde Park, New York, USA.
authors: Divya
authors: D
authors: Salhan
authors: Shresh
authors: S
authors: Pathak
authors: Mohammad
authors: M
authors: Husain
authors: Pranai
authors: P
authors: Tandon
authors: Dileep
authors: D
authors: Kumar
authors: Ashwani
authors: A
authors: Malhotra
authors: Leonard G
authors: LG
authors: Meggs
authors: Pravin C
authors: PC
authors: Singhal
mesh_terms: D016263:AIDS-Associated Nephropathy / Q000209:etiology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002374:Catalase / Q000096:biosynthesis; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015658:HIV Infections / Q000235:genetics; D015497:HIV-1; D007684:Kidney Tubules / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins / Q000378:metabolism*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013482:Superoxide Dismutase / Q000096:biosynthesis
chemical_list: D000975:Antioxidants; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D017382:Reactive Oxygen Species; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D002374:Catalase; D013482:Superoxide Dismutase