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

Abstract

Introduction: Survivors of severe burns suffer lifetime neuroinflammatory consequences manifested by higher incidence of major depression and neurodegenerative disease. In a scald model, nephrilin peptide has previously been shown to protect rats from loss of lean body mass, kidney function and glycaemic control, complications that have also been shown to endure in burn patient populations. Nephrilin’s mechanism of action has been suggested to involve protection from excessive oxidative stress. Methods: Using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) amplification of transcripts in total RNA extracted from dorsal root ganglia 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 central nervous system (CNS). We use these data to explore the central role of oxidative stress in astrogliosis, immunosuppression and mitochondrial homeostasis. Results and Discussion: Rats that received nephrilin treatment (4 mg/kg by subcutaneous bolus injection once daily for seven days after scald injury) showed significantly reduced elevations in gene expression of some key genes such as NOX2, GFAP, AQP4 and RAC1, but not of others such as NOX4, STEAP4, ARG1 and CCL2. Conclusion: The implications of these data with reference to nephrilin’s potential clinical utility for mitigating the enduring effects of burn trauma on the CNS are discussed. Nephrilin reduces the expression of some genes implicated in neurodegeneration after burn insult. Lay Summary Nephrilin peptide is a novel treatment for short- and long-term systemic effects of burn trauma. This study measures the capability of nephrilin to address post-traumatic neurodegenerative disease by looking at the expression of genes in the central nervous system, in a rat scald model. Nephrilin appears to have beneficial effects by reducing the expression of some key genes known to be relevant in neurodegenerative processes, but not others.

Lobe-specific modulation of B16MET melanoma lung metastases by nephrilin peptide

“…Severe burn trauma is associated with secondary systemic effects including hyper inflammation, hypercatabolism, sepsis, organ failure, loss of glycemic control, delayed wound healing, and cognitive deficits [3][4][5][6][7][8] . We have demonstrated the efficacy of nephrilin peptide in combating many of these pleiotropic effects in burn trauma as well as in several rodent models of metabolic and xenobiotic stress [9][10][11][12][13][14] . When nephrilin peptide is injected subcutaneously into rodents, its Protor sequence is believed to reduce oxidative stress in target tissues by modulation of Rac1 phosphorylation and, more speculatively, its IGFBP3 sequence may mediate homeostatic immunomodulatory functions in addition to its described transporter functions [12] .…”

“…Nephrilin treatment following burn injury reverses epigenetic and signaling changes in kidney tissue that lead to the activation of Rac1, and lowers elevations in markers of systemic oxidative stress such as urinary 8-isoprostane and plasma OHDG [10][11][12] . Besides, an analysis of gene expression in the CNS after burn injury showed that nephrilin beneficially modulated the expression of genes associated with astrocytosis, oxidative stress, and immunosuppression [13] . Trauma is characterized by the co-existence of pro-inflammatory and immunosuppression phenomena, strikingly reminiscent of what has long been described for metastatic niche formation [15,16] .…”

Covalent modification of nephrilin peptide with valproic acid increases its efficacy as a therapeutic in burn trauma

“…In a recent publication we describe the variables most reliably modulated by nephrilin in the rat scald model, these variables falling into in seven distinct efficacy categories [ 12 , 13 ]. In addition, an analysis of gene expression in the central nervous system after burn injury showed that nephrilin beneficially modulated the expression of genes associated with astrocytosis, oxidative stress and immunosuppression [ 14 ].…”