title: Rapamycin-induced modulation of HIV gene transcription attenuates progression of HIVAN.
abstract: HIV-associated nephropathy (HIVAN) is the manifestation of HIV gene expression by kidney cells in the presence of specific host factors. Recently, rapamycin (sirolimus) has been demonstrated to modulate the progression of HIVAN. We hypothesized that rapamycin would modulate the progression of HIVAN by attenuating HIV gene expression. To test our hypothesis, three weeks old Tg26 mice (n=6) were administered either vehicle or rapamycin (5 mg/kg, every other day, intraperitoneal) for eight weeks. At the end of the experimental period, the kidneys were harvested. In in vitro studies, human podocytes were transduced with either HIV-1 (NL4-3) or empty vector (EV), followed by treatment with either vehicle or rapamycin. Total RNA and proteins were extracted from renal tissues/cellular lysates and HIV gene transcription/translation was measured by real time PCR and Western blotting studies. Renal histological slides were graded for glomerular sclerosis and tubular dilatation with microcyst formation. Rapamycin attenuated both glomerular and tubular lesions in Tg26 mice. Rapamycin decreased transcription of HIV genes both in renal tissues as well as in HIV-1 transduced podocytes. Our data strongly indicate that HIV-1 long terminal repeat-mediated transcriptional activity was targeted by rapamycin. Rapamycin enhanced podocyte NF-κB and CREB activities but then it decreased AP-1 binding activity. Since expression of HIV genes by kidney cells has been demonstrated to be the key factor in the development HIVAN, it appears that rapamycin-induced altered transcription of HIV genes might have partly contributed to its disease modulating effects.
authors.affiliation: Department of Medicine, Feinstein Institute for Medical Research, Hofstra North Shore LIJ Medical School, NY, USA.
authors.forename: Partab
authors.initials: P
authors.lastname: Rai
authors.forename: Andrei
authors.initials: A
authors.lastname: Plagov
authors.forename: Dileep
authors.initials: D
authors.lastname: Kumar
authors.forename: Shresh
authors.initials: S
authors.lastname: Pathak
authors.forename: Kamesh R
authors.initials: KR
authors.lastname: Ayasolla
authors.forename: Amrita K
authors.initials: AK
authors.lastname: Chawla
authors.forename: Peter W
authors.initials: PW
authors.lastname: Mathieson
authors.forename: Moin A
authors.initials: MA
authors.lastname: Saleem
authors.forename: Mohammad
authors.initials: M
authors.lastname: Husain
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 / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000821:virology; D007678:Kidney Glomerulus / Q000473:pathology / Q000821:virology; D007684:Kidney Tubules / Q000473:pathology / Q000821:virology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D050199:Podocytes / Q000187:drug effects / Q000821:virology; D012598:Sclerosis; D020123:Sirolimus / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D020123:Sirolimus