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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Aldosterone Negatively Regulates Nrf2 Activity: An Additional Mechanism Contributing to Oxidative Stress and Vascular Dysfunction by Aldosterone

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Author(s):
Rodrigues, Daniel [1] ; Costa, Tiago J. [1] ; Silva, Josiane F. [1] ; Neto, Jose Teles de Oliveira [1] ; Alves, Juliano V. [1] ; Fedoce, Aline G. [1] ; Costa, Rafael Menezes [2] ; Tostes, Rita C. [1]
Total Authors: 8
Affiliation:
[1] Univ Sao Paulo, Dept Pharmacol, Ribeirao Preto Med Sch, BR-14049900 Ribeirao Preto - Brazil
[2] Fed Univ Jatai, Hlth Sci Special Acad Unit, BR-75804020 Jatai - Brazil
Total Affiliations: 2
Document type: Journal article
Source: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 22, n. 11 JUN 2021.
Web of Science Citations: 0
Abstract

High levels of aldosterone (Aldo) trigger oxidative stress and vascular dysfunction independent of effects on blood pressure. We sought to determine whether Aldo disrupts Nrf2 signaling, the main transcriptional factor involved in antioxidant responses that aggravate cell injury. Thoracic aorta from male C57Bl/6J mice and cultured human endothelial cells (EA.hy926) were stimulated with Aldo (100 nM) in the presence of tiron {[}reactive oxygen species (ROS) scavenger, eplerenone {[}mineralocorticoid receptor (MR) antagonist], and L-sulforaphane (SFN; Nrf2 activator). Thoracic aortas were also isolated from mice infused with Aldo (600 mu g/kg per day) for 14 days. Aldo decreased endothelium-dependent vasorelaxation and increased ROS generation, effects prevented by tiron and MR blockade. Pharmacological activation of Nrf2 with SFN abrogated Aldo-induced vascular dysfunction and ROS generation. In EA.hy926 cells, Aldo increased ROS generation, which was prevented by eplerenone, tiron, and SFN. At short times, Aldo-induced ROS generation was linked to increased Nrf2 activation. However, after three hours, Aldo decreased the nuclear accumulation of Nrf2. Increased Keap1 protein expression, but not activation of p38 MAPK, was linked to Aldo-induced reduced Nrf2 activity. Arteries from Aldo-infused mice also exhibited decreased nuclear Nrf2 and increased Keap1 expression. Our findings suggest that Aldo reduces vascular Nrf2 transcriptional activity by Keap1-dependent mechanisms, contributing to mineralocorticoid-induced vascular dysfunction. (AU)

FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
Grantee:Fernando de Queiroz Cunha
Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
FAPESP's process: 18/05298-1 - Contribution of the transcription factor Nrf2 for the vascular alterations associated with arterial hypertension induced by aldosterone
Grantee:Daniel Rodrigues
Support Opportunities: Scholarships in Brazil - Scientific Initiation