Altered expression pattern of Nrf2/HO-1 axis during accelerated-senescence in HIV-1 transgenic rat

Abstract

Chronic oxidative stress plays a central role in the pathogenesis of many diseases, including HIV-1 associated disorders. Concomitantly with the decline of endogenous antioxidant systems, it was reported that HIV-1-related proteins increase the production of radical species in cells and tissues that are not directly infected by the virus. In the context of HIV-1 infection, the role of Nrf2, a key transcription factor that contributes to the maintenance of cellular redox homeostasis, remains largely uncharacterized. One of the major stress-responsive player regulated by Nrf2 is the antioxidant enzyme HO-1. The Nrf2/HO-1 axis constitutes a crucial cell survival mechanism to counteract oxidative stress and inflammation. The present study aims to investigate the age-related patterns of Nrf2 and HO-1 in different brain regions and tissues of HIV-1 transgenic rat. Since HIV-1 induces an accelerated aging and the redox imbalance may actively promote senescence, we also evaluated the senescence phenotype-switching by quantifying levels of β-galactosidase activity. Our results showed changes in gene expression, with different trends depending on the brain regions and tissues examined. However, compared to age-matched controls, we observed in HIV-1 transgenic rats a significant reduction in the protein levels of Nrf2 and HO-1, suggesting a weakening in the protection exerted by Nrf2/HO-1 system. Moreover, we show that senescence occurs more rapidly in HIV-1 transgenic rats than in control animals. To our knowledge this is the first in vivo report showing the involvement of Nrf2/HO-1 pathway in a rat model of HIV-1.

HIV-Tat Induces the Nrf2/ARE Pathway through NMDA Receptor-Elicited Spermine Oxidase Activation in Human Neuroblastoma Cells

“…It is important to take into account that the activation of an antioxidant response is not only regulated by the induction of Nrf2 but also by post-induction responses that tightly control Nrf2 activation and repression back to the basal state, finally ‘switching off’ Nrf2-activated gene expression [ 15 ]. Notably, HIV-1 induces accelerated aging, and the redox imbalance may actively promote senescence [ 31 ]. Compared to age-matched controls, HIV-1 transgenic rats have been shown to have a significant reduction in the protein levels of Nrf2 and HO-1, suggesting a weakening in the protection exerted by the Nrf2/HO-1 system [ 31 ].…”

Progressive Rotavirus Infection Downregulates Redox-Sensitive Transcription Factor Nrf2 and Nrf2-Driven Transcription Units

“…RSV-associated oxidative stress and associated pathophysiology, on the other hand, have been attributed to abrogated activation of the Nrf2/ARE pathway because of proteasomal degradation of Nrf2 by a SUMO-specific E3 ubiquitin ligase RING finger protein 4 (RNF4) [117,118]. Interestingly, differential influence of viral infection on the Nrf2/ARE pathway is becoming prevalent where context-dependent downregulation of the cellular antioxidant defense has been reported for HBV [119], HCV [120], HIV [121][122][123][124], and IAV [125] infection.…”

The unfolded protein response and cellular senescence. A Review in the Theme: Cellular Mechanisms of Endoplasmic Reticulum Stress Signaling in Health and Disease

“…This could operate through one of the targets of the PERK kinase, the NRF2 transcription factor that controls the expression of genes that maintain the redox homeostasis (31). Recently, a study described an altered expression of NRF2 and HO-1, one of its redox controlling genes, during HIV-1-induced premature senescence in rat tissues (33).…”