Abstract
Objective and designTo 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.MaterialThe 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.MethodsAnimals received daily subcutaneous bolus injections of saline or 4 mg/kg nephrilin. Tissues were assayed by ELISA, gene arrays and immunohistochemical staining.ResultsNephrilin 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 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.ConclusionsTaken together, our results suggest a role for mTORC2 in the inflammatory-oxidative responses to stress.
Highlights
Under stress, mammals unleash inflammatory cytokines and cellular reactive oxygen species via linked mechanisms that are only partially understood [1, 2]
Taken together, our results suggest a role for mammalian target of rapamycin 2 (mTORC2) in the inflammatory-oxidative responses to stress
We explored the effect of sub-cutaneously administered nephrilin in three of these models glycerol, gentamycin and cisplatin
Summary
Mammals unleash inflammatory cytokines and cellular reactive oxygen species via linked mechanisms that are only partially understood [1, 2]. 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]. 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 been suggested for disease conditions ranging from diabetes to cancer [7, 8]. We are interested in investigating conserved mechanisms that may link stress to dysfunctional inflammation and oxidative circuitry
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
