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mTOR Plays a Critical Role in p53-induced Oxidative Kidney Cell Injury in HIVAN.

Authors: Rai, P  Plagov, A  Lan, X  Chandel, N  Singh, T  Lederman, R  Ayasolla, KR  Mathieson, PW  Saleem, MA  Husain, M  Malhotra, A  Chander, PN  Singhal, PC 
Citation: Rai P, etal., Am J Physiol Renal Physiol. 2013 May 15.
Pubmed: (View Article at PubMed) PMID:23678040
DOI: Full-text: DOI:10.1152/ajprenal.00135.2013

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, down stream signaling, and kidney cell injury both in in vivo and in vitro studies. Inhibition of the mTOR pathway resulted into in Tg26 mice down regulation of renal tissue p53 expression, associated down stream signaling, and decreased number of sclerosed glomeruli, tubular microcysts, apoptosed, and 8-OHdG +ve cells in Tg26 mice. mTOR inhibition not only attenuated kidney cell expression of p66ShcA and phospho-p66ShcA but also reactivated redox-sensitive stress response program in the form of enhanced expression of MnSOD and catalase. In in vitro studies, the mTOR inhibitor also provided protection against HIV-induced podocyte apoptosis. Moreover, mTOR inhibition down regulated HIV-induced podocyte (HP/HIV) p53 expression. Since HP/HIV silenced for mTOR displayed 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 HIV milieu.

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RGD Object Information
RGD ID: 7245474
Created: 2013-06-05
Species: All species
Last Modified: 2013-06-05
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.