title: HIV-1 promotes renal tubular epithelial cell protein synthesis: role of mTOR pathway.
abstract: Tubular cell HIV-infection has been reported to manifest in the form of cellular hypertrophy and apoptosis. In the present study, we evaluated the role of mammalian target of rapamycin (mTOR) pathway in the HIV induction of tubular cell protein synthesis. Mouse proximal tubular epithelial cells (MPTECs) were transduced with either gag/pol-deleted NL4-3 (HIV/MPTEC) or empty vector (Vector/MPTEC). HIV/MPTEC showed enhanced DNA synthesis when compared with Vector/MPTECs by BRDU labeling studies. HIV/MPTECs also showed enhanced production of β-laminin and fibronection in addition to increased protein content per cell. In in vivo studies, renal cortical sections from HIV transgenic mice and HIVAN patients showed enhanced tubular cell phosphorylation of mTOR. Analysis of mTOR revealed increased expression of phospho (p)-mTOR in HIV/MPTECs when compared to vector/MPTECs. Further downstream analysis of mTOR pathway revealed enhanced phosphorylation of p70S6 kinase and associated diminished phosphorylation of eEF2 (eukaryotic translation elongation factor 2) in HIV/MPTECs; moreover, HIV/MPTECs displayed enhanced phosphorylation of eIF4B (eukaryotic translation initiation factor 4B) and 4EBP-1 (eukaryotic 4E binding protein). To confirm our hypothesis, we evaluated the effect of rapamycin on HIV-induced tubular cell downstream signaling. Rapamycin not only attenuated phosphorylation of p70S6 kinase and associated down stream signaling in HIV/MPTECs but also inhibited HIV-1 induced tubular cell protein synthesis. These findings suggest that mTOR pathway is activated in HIV-induced enhanced tubular cell protein synthesis and contributes to tubular cell hypertrophy.
authors.affiliation: Department of Medicine, North Shore LIJ Health System, New York, New York, United States of America.
authors.forename: Shabina
authors.initials: S
authors.lastname: Rehman
authors.forename: Mohammad
authors.initials: M
authors.lastname: Husain
authors.forename: Anju
authors.initials: A
authors.lastname: Yadav
authors.forename: Balakuntalam S
authors.initials: BS
authors.lastname: Kasinath
authors.forename: Ashwani
authors.initials: A
authors.lastname: Malhotra
authors.forename: Pravin C
authors.initials: PC
authors.lastname: Singhal
mesh_terms: D016263:AIDS-Associated Nephropathy / Q000378:metabolism / Q000821:virology; D000818:Animals; D004247:DNA / Q000096:biosynthesis; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D005353:Fibronectins / Q000096:biosynthesis; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D007684:Kidney Tubules / Q000473:pathology*; D007797:Laminin / Q000096:biosynthesis; D051379:Mice; D008954:Models, Biological; D020652:Peptide Elongation Factor 2 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D035463:Pol1 Transcription Initiation Complex Proteins / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D005353:Fibronectins; D007797:Laminin; D020652:Peptide Elongation Factor 2; D035463:Pol1 Transcription Initiation Complex Proteins; C063844:transcription factor UBF; D004247:DNA; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus