Mammalian target of rapamycin complex 2 regulates inflammatory response to stress
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Inflammation Research
ORIGINAL RESEARCH PAPER
Mammalian target of rapamycin complex 2 regulates inflammatory response to stress Desmond Mascarenhas • Sheri Routt Baljit K. Singh
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Received: 21 November 2011 / Revised: 25 July 2012 / Accepted: 31 July 2012 Ó The Author(s) 2012. This article is published with open access at Springerlink.com
Abstract Objective and design To explore the role of mammalian target of rapamycin 2 (mTORC2) in the activation of inflammatory and oxidative responses in rodent models of acute injury and metabolic stress. Material The impact of nephrilin, an inhibitor of mTORC2 complex, was assessed in three CD-1 mouse models of acute xenobiotic stress and in a hypertensive Dahl rat model of metabolic stress. Methods Animals received daily subcutaneous bolus injections of saline or 4 mg/kg nephrilin. Tissues were assayed by ELISA, gene arrays and immunohistochemical staining. Results Nephrilin significantly inhibited elevations in plasma tumor necrosis factor-alpha, kidney substance P, and CX3CR1, and urinary lipocalin-2 [urinary neutrophil gelatinase-associated lipocalin (uNGAL)] in models of acute xenobiotic stress. UCHL1 gene expression levels dropped and plasma HMGB1 levels rose in the rhabdomyolysis model. Both effects were reversed by nephrilin. The inhibitor also blocked diet-induced elevations of uNGAL and albumin-creatinine ratio (UACR) as well as kidney tissue phosphorylation of PKC-beta-2-T641 and
Responsible Editor: Artur Bauhofer. D. Mascarenhas (&) Mayflower Organization for Research and Education, 525 Del Rey Avenue, Suite B, Sunnyvale, CA 94085, USA e-mail: [email protected] S. Routt Piedmont Research Center, Morrisville, NC, USA D. Mascarenhas B. K. Singh Protigen Inc, Sunnyvale, CA, USA
p66shc-S36, and reduced dark ring-like staining of nuclei by anti-phos-p66shc-S36 antibody in frozen sections of diseased kidneys from hypertensive Dahl rats fed an 8 % NaCl diet for 4 weeks. Conclusions Taken together, our results suggest a role for mTORC2 in the inflammatory-oxidative responses to stress. Keywords Nephrilin mTORC2 Substance P NGAL UCHL1
Introduction Under stress, mammals unleash inflammatory cytokines and cellular reactive oxygen species via linked mechanisms that are only partially understood [1, 2]. In humans, systemic inflammatory responses to traumatic stress can lead to sepsis and high mortality in the intensive care unit, especially when marked by kidney injury [3]. Urinary neutrophil gelatinase-associated lipocalin (uNGAL) has been used as a reliable early marker of such injury in critical care settings [4, 5]. The inflammatory and oxidative processes underlying the pathology of these life-threatening conditions are not well characterized, but are hallmarks of a variety of insults including ischemic injury, rhabdomyolysis, burns, and xenobiotic and physical trauma [6]. A parallel phenomenon of underlying oxidative damage triggered by stress has also been suggested for disease conditions ranging from diabetes to cancer [7, 8]. We are interested
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