Epigenetic memory of oxidative stress

Does nephrilin exert its protective effects via Rac1?

Desmond D. Mascarenhas, David Herndon, Istvan Arany

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)97-106
Number of pages10
JournalBiologics: Targets and Therapy
Volume11
DOIs
StatePublished - Jul 17 2017

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Epigenomics
Oxidative Stress
Kidney
Proximal Kidney Tubule
Epithelial Cells
Urine
Nicotine
Histone Code
Animal Models
Fibroblasts
Skin
Peptides
Gene Regulatory Networks
NADPH Oxidase
Wounds and Injuries
Xenobiotics
DNA Methylation
Reactive Oxygen Species
Collagen
Phosphorylation

Keywords

  • 8-isoprostane
  • Burn injury
  • Epigenetic
  • Nephrilin
  • Rac1
  • Rictor

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Oncology
  • Gastroenterology
  • Pharmacology (medical)

Cite this

Epigenetic memory of oxidative stress : Does nephrilin exert its protective effects via Rac1? / Mascarenhas, Desmond D.; Herndon, David; Arany, Istvan.

In: Biologics: Targets and Therapy, Vol. 11, 17.07.2017, p. 97-106.

Research output: Contribution to journalArticle

Mascarenhas, Desmond D. ; Herndon, David ; Arany, Istvan. / Epigenetic memory of oxidative stress : Does nephrilin exert its protective effects via Rac1?. In: Biologics: Targets and Therapy. 2017 ; Vol. 11. pp. 97-106.
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