Nrf2 Activation Does Not Protect from Aldosterone-Induced Kidney Damage in Mice

Area of Science:

• Nephrology
• Molecular Biology
• Oxidative Stress Research

Background:

• Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a crucial role in cellular defense against oxidative stress.
• Nrf2 signaling is often impaired in chronic kidney disease (CKD), suggesting therapeutic potential for its activation.
• Aldosterone (Aldo) is implicated in the pathogenesis of renal injury.

Purpose of the Study:

• To investigate the therapeutic efficacy of Nrf2 activation against aldosterone-induced renal injury.
• To explore the mechanisms underlying Nrf2 regulation in the context of renal damage.

Main Methods:

• Utilized wild-type (WT) mice, genetically modified Nrf2-upregulated mice (Nrf2ꜛ), and WT mice treated with the Nrf2 activator sulforaphane (Sulf).
• Administered aldosterone (Aldo) to mice for 4 weeks to induce renal injury.
• Assessed kidney pathology, urinary albumin, oxidative damage markers (8-OHdG, 15-isoprostane F_2t), tubule damage marker NGAL, and expression of Nrf2 and its target genes (NQO1, HO1), as well as GSK3β.

Main Results:

• Aldosterone treatment led to increased kidney weight, albuminuria, and tissue damage in all groups.
• Genetic or pharmacological Nrf2 activation did not prevent oxidative damage or renal injury.
• Aldosterone increased Nrf2 levels and phosphorylation in WT mice, but decreased Nrf2 target gene expression.
• GSK3β, a promoter of Nrf2 degradation, was upregulated in aldosterone-treated WT mice.

Conclusions:

• Neither genetic nor pharmacological activation of Nrf2 could ameliorate aldosterone-induced renal injury in mice.
• The lack of therapeutic effect may be attributed to the induction of negative regulators of Nrf2 by aldosterone.
• These findings highlight the complexity of Nrf2 regulation in kidney injury and suggest limitations to Nrf2-targeted therapies in this context.