PMID- 23678040
OWN - NLM
STAT- MEDLINE
DCOM- 20131017
LR  - 20220129
IS  - 1522-1466 (Electronic)
IS  - 1931-857X (Print)
IS  - 1522-1466 (Linking)
VI  - 305
IP  - 3
DP  - 2013 Aug 1
TI  - mTOR plays a critical role in p53-induced oxidative kidney cell injury in HIVAN.
PG  - F343-54
LID - 10.1152/ajprenal.00135.2013 [doi]
AB  - 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.
FAU - Rai, Partab
AU  - Rai P
AD  - Department of Medicine, Feinstein Institute for Medical Research, Hofstra North 
      Shore LIJ Medical School, Great Neck, NY, USA.
FAU - Plagov, Andrei
AU  - Plagov A
FAU - Lan, Xiqian
AU  - Lan X
FAU - Chandel, Nirupama
AU  - Chandel N
FAU - Singh, Tejinder
AU  - Singh T
FAU - Lederman, Rivka
AU  - Lederman R
FAU - Ayasolla, Kamesh R
AU  - Ayasolla KR
FAU - Mathieson, Peter W
AU  - Mathieson PW
FAU - Saleem, Moin A
AU  - Saleem MA
FAU - Husain, Mohammad
AU  - Husain M
FAU - Malhotra, Ashwani
AU  - Malhotra A
FAU - Chander, Praveen N
AU  - Chander PN
FAU - Singhal, Pravin C
AU  - Singhal PC
LA  - eng
GR  - G0800200/MRC_/Medical Research Council/United Kingdom
GR  - R01 DK-084910/DK/NIDDK NIH HHS/United States
GR  - R01 DK-083931/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20130515
PL  - United States
TA  - Am J Physiol Renal Physiol
JT  - American journal of physiology. Renal physiology
JID - 100901990
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 88847-89-6 (8-Hydroxy-2'-Deoxyguanosine)
RN  - EC 1.11.1.6 (Catalase)
RN  - EC 1.15.1.1 (Superoxide Dismutase)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - G9481N71RO (Deoxyguanosine)
SB  - IM
MH  - 8-Hydroxy-2'-Deoxyguanosine
MH  - AIDS-Associated Nephropathy/*pathology
MH  - Acute Kidney Injury/*etiology/*pathology
MH  - Animals
MH  - Apoptosis/physiology
MH  - Catalase/metabolism
MH  - Deoxyguanosine/analogs & derivatives/metabolism
MH  - Gene Silencing
MH  - HIV Infections/*complications/*pathology
MH  - Humans
MH  - Immunohistochemistry
MH  - In Situ Nick-End Labeling
MH  - Mice
MH  - Mice, Transgenic
MH  - Oxidative Stress/*physiology
MH  - Podocytes/pathology
MH  - Rats
MH  - Real-Time Polymerase Chain Reaction
MH  - Signal Transduction/physiology
MH  - Superoxide Dismutase/metabolism
MH  - TOR Serine-Threonine Kinases/*physiology
MH  - Tumor Suppressor Protein p53/*physiology
PMC - PMC3742868
OTO - NOTNLM
OT  - apoptosis
OT  - mTOR
OT  - oxidative stress
OT  - rapamycin
OT  - renal tubular cells
EDAT- 2013/05/17 06:00
MHDA- 2013/10/18 06:00
PMCR- 2014/08/01
CRDT- 2013/05/17 06:00
PHST- 2013/05/17 06:00 [entrez]
PHST- 2013/05/17 06:00 [pubmed]
PHST- 2013/10/18 06:00 [medline]
PHST- 2014/08/01 00:00 [pmc-release]
AID - ajprenal.00135.2013 [pii]
AID - F-00135-2013 [pii]
AID - 10.1152/ajprenal.00135.2013 [doi]
PST - ppublish
SO  - Am J Physiol Renal Physiol. 2013 Aug 1;305(3):F343-54. doi: 
      10.1152/ajprenal.00135.2013. Epub 2013 May 15.