<div>Epigenetic memory of oxidative stress: does nephrilin exert its protective effects via Rac1?</div>

Abstract

AimNephrilin peptide, a designed inhibitor of Rictor complex (mTORC2), exerts pleiotropic protective effects in metabolic, xenobiotic and traumatic stress models. Stress can generate enduring epigenetic changes in gene function. In this work we examine the possibility that nephrilin treatment protects against acute and enduring global changes in oxidative metabolism, with a focus on the Rictor-complex-mediated activation of Rac1, a subunit of NADPH oxidase (Nox) via PKCs, Prex1 and p66shc.MethodsGiven the wide range of animal models in which nephrilin peptide has previously demonstrated effectiveness in vivo, we chose three different experimental systems for this investigation: dermal fibroblasts, renal proximal tubule epithelial cells (PTECs), and kidney tissue and urine from an animal model of burn trauma in which nephrilin was previously shown to prevent loss of kidney function.Results(1) Nephrilin protects dermal fibroblasts from loss of viability and collagen synthesis after ultraviolet A (UV-A) or H2O2 insult. (2) Nephrilin reduces reactive oxygen species (ROS) formation by H2O2–treated (PTECs) with or without nicotine pretreatment. Using RNA arrays and pathway analysis we demonstrate that nicotine and H2O2-treated PTECs specifically induced Rac1 gene networks in these cells. (3) Using kidney tissue and urine from the burn trauma model we demonstrate significant elevations of [a] 8-aminoprostane in urine; [b] kidney tissue histone modification and DNA methylation; and [c] post-transcriptional phosphorylation events consistent with Rac1 activation in kidney tissue.ConclusionNephrilin protects against oxidative stress, possibly by modulating the activation of Rac1.

Stress, Brain Wiring and the Economy

“…A recent study showed that a severely stressful event (thermal injury) in rats generates enduring epigenetic changes in a pathway associated with mitochondrial oxidative metabolism, the Rac1/NADPH oxidase (Nox) pathway [18]. Markers of oxidative stress, such as 8-isoprostane and other markers of lipid peroxidation, are often elevated in neuroinflammation and CNS dysfunction [19,20].…”

“…Both PKCs and Prex serve to hyper-activate Rac1. In some studies, nuclear translocation of Rictor appears to control both neuroinflammation and oxidative stress via Rac1 hyper-activation [18,[21][22][23][24].…”

“…In one study, nephrilin injected into rats reversed an enduring elevation in PKC and calcitonin-gene related peptide (CGRP), a major regulator of neuroinflammation and pain, caused by traumatic stress in dorsal root ganglia [21]. Data from kidney tissues implicates both global (histone-3 acetylation) and local (DNA methylation) effects in the action of nephrilin in this model [18]. Similar epigenetic effects on dorsal root ganglia have not yet been demonstrated.…”

Transcriptional re-programming in rat central nervous system two weeks after burn trauma: the impact of nephrilin treatment on the expression of oxidative stress-related genes

“…Nephrilin's mechanism of action has previously been shown to involve protection from excessive oxidative stress in kidney. 7 In this study, using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) amplification of transcripts in total RNA extracted from dorsal root ganglia (DRG) of male rats 14 days after exposure to thermal insult, we query the relative levels of expression of 34 genes believed to be associated with oxidative stress biology in the CNS, with an emphasis on astrogliosis, immunosuppression and mitochondrial homeostasis. These phenomena appear to be inextricably linked to one another, and to CNS oxidative stress post-traumatic insult in a variety of contexts.…”

“…Nephrilin’s mechanism of action has previously been shown to involve protection from excessive oxidative stress in kidney. 7 …”