Activation of the Nrf2/HO-1 pathway restores N-acetylcysteine-induced impairment of the hypothalamus-pituitary-adrenal axis negative feedback by up-regulating GRα expression and down-regulating GRβ expression into pituitary glands
We previously showed that antioxidants induced an impairment of negative feedback of the hypothalamus-pituitary-adrenal (HPA) axis in rats, in parallel to a down-regulation of the glucocorticoid receptor (GR) and nuclear factor erythroid 2-related factor 2 (Nrf2) expression in the pituitary gland. T...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2025.1500630/full |
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| author | Amanda Silva Chaves Raíssa Duarte Ventura Maria Florencia Pacini Nathalia Santos Magalhães Patrícia Machado Rodrigues e Silva Marco Aurélio Martins Ana Rosa Pérez Vinicius Frias Carvalho Vinicius Frias Carvalho Vinicius Frias Carvalho Vinicius Frias Carvalho |
| author_facet | Amanda Silva Chaves Raíssa Duarte Ventura Maria Florencia Pacini Nathalia Santos Magalhães Patrícia Machado Rodrigues e Silva Marco Aurélio Martins Ana Rosa Pérez Vinicius Frias Carvalho Vinicius Frias Carvalho Vinicius Frias Carvalho Vinicius Frias Carvalho |
| author_sort | Amanda Silva Chaves |
| collection | DOAJ |
| description | We previously showed that antioxidants induced an impairment of negative feedback of the hypothalamus-pituitary-adrenal (HPA) axis in rats, in parallel to a down-regulation of the glucocorticoid receptor (GR) and nuclear factor erythroid 2-related factor 2 (Nrf2) expression in the pituitary gland. This study evaluated the role of the Nrf2-heme-oxygenase-1 (HO-1) pathway on the impairment of the negative feedback of the HPA axis induced by N-acetylcysteine (NAC). Male Swiss-Webster mice were orally supplemented with NAC for 5 consecutive days. The Nrf2-HO-1 pathway activator cobalt protoporphyrin IX (CoPPIX) was injected intraperitoneally on days 2 and 5 after the starting of NAC supplementation. NAC reduced the expression of Nrf2 in the pituitary of mice. Furthermore, NAC induced adrenal enlargement and hypercorticoidism, along with a decrease in the GRα expression and an increase of GRβ expression in the pituitary gland. Treatment with CoPPIX reduced adrenal enlargement, systemic corticosterone levels, and GRβ expression in the pituitary gland of mice supplemented with NAC, besides increasing the expression of GRα. CoPPIX treatment also restored the failure in the negative feedback of the HPA axis induced by NAC. In conclusion, these findings showed that NAC reduced the Nrf2-HO-1 pathway activation in the pituitary gland, in a mechanism probably related to a local downregulation of GRα and an up-regulation of GRβ, leading to a failure of negative feedback of the HPA axis and consequently to the hyperactivity of this neuroendocrine axis. |
| format | Article |
| id | doaj-art-76a465dfa906491cb6868c69d71e1e36 |
| institution | Kabale University |
| issn | 1664-2392 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Endocrinology |
| spelling | doaj-art-76a465dfa906491cb6868c69d71e1e362025-01-27T06:40:07ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922025-01-011610.3389/fendo.2025.15006301500630Activation of the Nrf2/HO-1 pathway restores N-acetylcysteine-induced impairment of the hypothalamus-pituitary-adrenal axis negative feedback by up-regulating GRα expression and down-regulating GRβ expression into pituitary glandsAmanda Silva Chaves0Raíssa Duarte Ventura1Maria Florencia Pacini2Nathalia Santos Magalhães3Patrícia Machado Rodrigues e Silva4Marco Aurélio Martins5Ana Rosa Pérez6Vinicius Frias Carvalho7Vinicius Frias Carvalho8Vinicius Frias Carvalho9Vinicius Frias Carvalho10Laboratory of Inflammation, Center for Research, Innovation, and Surveillance in Covid-19 and Health Emergencies, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, BrazilLaboratory of Inflammation, Center for Research, Innovation, and Surveillance in Covid-19 and Health Emergencies, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, BrazilInstitute of Clinical and Experimental Immunology (IDICER-CONICET UNR), Rosario, ArgentinaLaboratory of Inflammation, Center for Research, Innovation, and Surveillance in Covid-19 and Health Emergencies, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, BrazilLaboratory of Inflammation, Center for Research, Innovation, and Surveillance in Covid-19 and Health Emergencies, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, BrazilLaboratory of Inflammation, Center for Research, Innovation, and Surveillance in Covid-19 and Health Emergencies, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, BrazilInstitute of Clinical and Experimental Immunology (IDICER-CONICET UNR), Rosario, ArgentinaLaboratory of Inflammation, Center for Research, Innovation, and Surveillance in Covid-19 and Health Emergencies, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, BrazilNational Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, BrazilRio de Janeiro Research Network on Neuroinflammation (RENEURIN), Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, BrazilINOVA-IOC Network on Neuroimmunomodulation, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation, Rio de Janeiro, BrazilWe previously showed that antioxidants induced an impairment of negative feedback of the hypothalamus-pituitary-adrenal (HPA) axis in rats, in parallel to a down-regulation of the glucocorticoid receptor (GR) and nuclear factor erythroid 2-related factor 2 (Nrf2) expression in the pituitary gland. This study evaluated the role of the Nrf2-heme-oxygenase-1 (HO-1) pathway on the impairment of the negative feedback of the HPA axis induced by N-acetylcysteine (NAC). Male Swiss-Webster mice were orally supplemented with NAC for 5 consecutive days. The Nrf2-HO-1 pathway activator cobalt protoporphyrin IX (CoPPIX) was injected intraperitoneally on days 2 and 5 after the starting of NAC supplementation. NAC reduced the expression of Nrf2 in the pituitary of mice. Furthermore, NAC induced adrenal enlargement and hypercorticoidism, along with a decrease in the GRα expression and an increase of GRβ expression in the pituitary gland. Treatment with CoPPIX reduced adrenal enlargement, systemic corticosterone levels, and GRβ expression in the pituitary gland of mice supplemented with NAC, besides increasing the expression of GRα. CoPPIX treatment also restored the failure in the negative feedback of the HPA axis induced by NAC. In conclusion, these findings showed that NAC reduced the Nrf2-HO-1 pathway activation in the pituitary gland, in a mechanism probably related to a local downregulation of GRα and an up-regulation of GRβ, leading to a failure of negative feedback of the HPA axis and consequently to the hyperactivity of this neuroendocrine axis.https://www.frontiersin.org/articles/10.3389/fendo.2025.1500630/fullantioxidantsglucocorticoidGR isoformsHPA axisNrf-2 |
| spellingShingle | Amanda Silva Chaves Raíssa Duarte Ventura Maria Florencia Pacini Nathalia Santos Magalhães Patrícia Machado Rodrigues e Silva Marco Aurélio Martins Ana Rosa Pérez Vinicius Frias Carvalho Vinicius Frias Carvalho Vinicius Frias Carvalho Vinicius Frias Carvalho Activation of the Nrf2/HO-1 pathway restores N-acetylcysteine-induced impairment of the hypothalamus-pituitary-adrenal axis negative feedback by up-regulating GRα expression and down-regulating GRβ expression into pituitary glands Frontiers in Endocrinology antioxidants glucocorticoid GR isoforms HPA axis Nrf-2 |
| title | Activation of the Nrf2/HO-1 pathway restores N-acetylcysteine-induced impairment of the hypothalamus-pituitary-adrenal axis negative feedback by up-regulating GRα expression and down-regulating GRβ expression into pituitary glands |
| title_full | Activation of the Nrf2/HO-1 pathway restores N-acetylcysteine-induced impairment of the hypothalamus-pituitary-adrenal axis negative feedback by up-regulating GRα expression and down-regulating GRβ expression into pituitary glands |
| title_fullStr | Activation of the Nrf2/HO-1 pathway restores N-acetylcysteine-induced impairment of the hypothalamus-pituitary-adrenal axis negative feedback by up-regulating GRα expression and down-regulating GRβ expression into pituitary glands |
| title_full_unstemmed | Activation of the Nrf2/HO-1 pathway restores N-acetylcysteine-induced impairment of the hypothalamus-pituitary-adrenal axis negative feedback by up-regulating GRα expression and down-regulating GRβ expression into pituitary glands |
| title_short | Activation of the Nrf2/HO-1 pathway restores N-acetylcysteine-induced impairment of the hypothalamus-pituitary-adrenal axis negative feedback by up-regulating GRα expression and down-regulating GRβ expression into pituitary glands |
| title_sort | activation of the nrf2 ho 1 pathway restores n acetylcysteine induced impairment of the hypothalamus pituitary adrenal axis negative feedback by up regulating grα expression and down regulating grβ expression into pituitary glands |
| topic | antioxidants glucocorticoid GR isoforms HPA axis Nrf-2 |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2025.1500630/full |
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