title: mTOR plays a critical role in p53-induced oxidative kidney cell injury in HIVAN.
abstract: Oxidative stress has been implicated to contribute to HIV-induced kidney cell injury; however, the role of p53, a modulator of oxidative stress, has not been evaluated in the development of HIV-associated nephropathy (HIVAN). We hypothesized that mammalian target of rapamycin (mTOR) may be critical for the induction of p53-mediated oxidative kidney cell injury in HIVAN. To test our hypothesis, we evaluated the effect of an mTOR inhibitor, rapamycin, on kidney cell p53 expression, downstream signaling, and kidney cell injury in both in vivo and in vitro studies. Inhibition of the mTOR pathway resulted in downregulation of renal tissue p53 expression, associated downstream signaling, and decreased number of sclerosed glomeruli, tubular microcysts, and apoptosed and 8-hydroxy deoxyguanosine (8-OHdG)-positive (+ve) cells in Tg26 mice. mTOR inhibition not only attenuated kidney cell expression of p66ShcA and phospho-p66ShcA but also reactivated the redox-sensitive stress response program in the form of enhanced expression of manganese superoxide dismutase (MnSOD) and catalase. In in vitro studies, the mTOR inhibitor also provided protection against HIV-induced podocyte apoptosis. Moreover, mTOR inhibition downregulated HIV-induced podocyte (HP/HIV) p53 expression. Since HP/HIV silenced for mTOR displayed a lack of expression of p53 as well as attenuated podocyte apoptosis, this suggests that mTOR is critical for kidney cell p53 activation and associated oxidative kidney cell injury in the HIV milieu.
authors.affiliation: Department of Medicine, Feinstein Institute for Medical Research, Hofstra North Shore LIJ Medical School, Great Neck, NY, USA.
authors.forename: Partab
authors.initials: P
authors.lastname: Rai
authors.forename: Andrei
authors.initials: A
authors.lastname: Plagov
authors.forename: Xiqian
authors.initials: X
authors.lastname: Lan
authors.forename: Nirupama
authors.initials: N
authors.lastname: Chandel
authors.forename: Tejinder
authors.initials: T
authors.lastname: Singh
authors.forename: Rivka
authors.initials: R
authors.lastname: Lederman
authors.forename: Kamesh R
authors.initials: KR
authors.lastname: Ayasolla
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: Praveen N
authors.initials: PN
authors.lastname: Chander
authors.forename: Pravin C
authors.initials: PC
authors.lastname: Singhal
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D016263:AIDS-Associated Nephropathy / Q000473:pathology*; D058186:Acute Kidney Injury / Q000209:etiology* / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002374:Catalase / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D020868:Gene Silencing; D015658:HIV Infections / Q000150:complications* / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000502:physiology*; D050199:Podocytes / Q000473:pathology; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D013482:Superoxide Dismutase / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D016159:Tumor Suppressor Protein p53; D000080242:8-Hydroxy-2'-Deoxyguanosine; D002374:Catalase; D013482:Superoxide Dismutase; D058570:TOR Serine-Threonine Kinases; D003849:Deoxyguanosine
keywords: apoptosis; mTOR; oxidative stress; rapamycin; renal tubular cells