Epigenetic memory of oxidative stress: does nephrilin exert its protective effects via Rac1?

Desmond D Mascarenhas,1,2 David N Herndon,3 Istvan Arany4 1Mayflower Organization for Research & Education, Sunnyvale, CA, 2Transporin, Inc., Sunnyvale, CA, 3Department of Surgery, The University of Texas Medical Branch, and Shriners Hospitals for Children, Galveston, TX, 4Department of Pedi...

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Autores principales:	Mascarenhas DD, Herndon DN, Arany I
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2017
Materias:	nephrilin epigenetic Rac1 burn injury Rictor 8-isoprostane Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/07ddeac38c8f4ae8801b003839a1ffc8
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spelling	oai:doaj.org-article:07ddeac38c8f4ae8801b003839a1ffc82021-12-02T00:40:40ZEpigenetic memory of oxidative stress: does nephrilin exert its protective effects via Rac1?1177-5491https://doaj.org/article/07ddeac38c8f4ae8801b003839a1ffc82017-07-01T00:00:00Zhttps://www.dovepress.com/epigenetic-memory-of-oxidative-stress-does-nephrilin-exert-its-protect-peer-reviewed-article-BTThttps://doaj.org/toc/1177-5491Desmond D Mascarenhas,1,2 David N Herndon,3 Istvan Arany4 1Mayflower Organization for Research & Education, Sunnyvale, CA, 2Transporin, Inc., Sunnyvale, CA, 3Department of Surgery, The University of Texas Medical Branch, and Shriners Hospitals for Children, Galveston, TX, 4Department of Pediatrics, Division of Pediatric Nephrology, University of Mississippi Medical Center, Jackson, MS, USA Aim: Nephrilin 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. Methods: Given 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. Conclusion: Nephrilin protects against oxidative stress, possibly by modulating the activation of Rac1. Keywords: nephrilin, epigenetic, Rac1, burn injury, Rictor, 8-isoprostaneMascarenhas DDHerndon DNArany IDove Medical PressarticlenephrilinepigeneticRac1burn injuryRictor8-isoprostaneMedicine (General)R5-920ENBiologics: Targets & Therapy, Vol Volume 11, Pp 97-106 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	nephrilin epigenetic Rac1 burn injury Rictor 8-isoprostane Medicine (General) R5-920
spellingShingle	nephrilin epigenetic Rac1 burn injury Rictor 8-isoprostane Medicine (General) R5-920 Mascarenhas DD Herndon DN Arany I Epigenetic memory of oxidative stress: does nephrilin exert its protective effects via Rac1?
description	Desmond D Mascarenhas,1,2 David N Herndon,3 Istvan Arany4 1Mayflower Organization for Research & Education, Sunnyvale, CA, 2Transporin, Inc., Sunnyvale, CA, 3Department of Surgery, The University of Texas Medical Branch, and Shriners Hospitals for Children, Galveston, TX, 4Department of Pediatrics, Division of Pediatric Nephrology, University of Mississippi Medical Center, Jackson, MS, USA Aim: Nephrilin 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. Methods: Given 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. Conclusion: Nephrilin protects against oxidative stress, possibly by modulating the activation of Rac1. Keywords: nephrilin, epigenetic, Rac1, burn injury, Rictor, 8-isoprostane
format	article
author	Mascarenhas DD Herndon DN Arany I
author_facet	Mascarenhas DD Herndon DN Arany I
author_sort	Mascarenhas DD
title	Epigenetic memory of oxidative stress: does nephrilin exert its protective effects via Rac1?
title_short	Epigenetic memory of oxidative stress: does nephrilin exert its protective effects via Rac1?
title_full	Epigenetic memory of oxidative stress: does nephrilin exert its protective effects via Rac1?
title_fullStr	Epigenetic memory of oxidative stress: does nephrilin exert its protective effects via Rac1?
title_full_unstemmed	Epigenetic memory of oxidative stress: does nephrilin exert its protective effects via Rac1?
title_sort	epigenetic memory of oxidative stress: does nephrilin exert its protective effects via rac1?
publisher	Dove Medical Press
publishDate	2017
url	https://doaj.org/article/07ddeac38c8f4ae8801b003839a1ffc8
work_keys_str_mv	AT mascarenhasdd epigeneticmemoryofoxidativestressdoesnephrilinexertitsprotectiveeffectsviarac1 AT herndondn epigeneticmemoryofoxidativestressdoesnephrilinexertitsprotectiveeffectsviarac1 AT aranyi epigeneticmemoryofoxidativestressdoesnephrilinexertitsprotectiveeffectsviarac1
_version_	1718403536228712448

Epigenetic memory of oxidative stress: does nephrilin exert its protective effects via Rac1?

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