A novel role has been suggested for mineralocorticoid receptor (MR) activation in patients with sickle cell disease (SCD) that may induce increased circulating levels of endothelin-1 (ET-1).
The findings are from a study performed in Berkeley SCD (BERK) mice and published in the The FASEB Journal.
Among individuals with SCD and transgenic mouse models of the condition, elevated plasma concentrations of ET-1 are associated with disordered inflammatory, hematologic, and vascular responses. In fact, MR activation by aldosterone, a key component of the renin-angiotensin-aldosterone system, has been shown to control vascular reactivity and inflammation partially via increased expression of ET-1.
Recognizing that the role played by aldosterone/MR activation in patients with SCD remains to be elucidated, the researchers sought to explore whether MR blockade in an SCD mouse model would improve inflammation and hematologic parameters. They described the in vivo effects of the MR antagonist (MRA) eplerenone on vascular and hematologic parameters in a BERK mouse model of severe SCD in which increased oxidative stress; endothelial activation; elevated inflammatory cytokines, such as ET-1; leukocytosis; cardiomyopathy; glomerulosclerosis; and impaired urinary concentration were reported.
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The mice undergoing evaluation were randomized for 14 days to 1 of 2 regimens: chow containing 156 mg/kg of eplerenone (n=8) or regular mouse chow (control; n=9).
Results of the study demonstrated that MRA treatment with eplerenone was associated with the following:
- Significantly decreased ET-1 plasma levels (P =.04);
- A significantly improved red cell density gradient profile (P <.002); and
- Significantly increased mean corpuscular volume in erythrocytes (P <.02) and reticulocytes (P <.024).
Additional findings associated with MRA therapy included the following:
- Decreased Gardos channel activity;
- Reduced protein disulfide isomerase (PDI) activity and inflammatory markers;
- Increased PDI mRNA expression in human endothelial cells associated with ET-1;
- Significantly increased PDI mRNA levels (P <.01) and activity (P <.003) in endothelial cells linked to aldosterone;
- Decreased KCa3.1 activity in endothelial cells by PDI small interfering RNA (siRNA); and
- Inhibition of ET-1-stimulated production of reactive oxygen species in endothelial cells by PDI siRNA therapy.
“Our results suggest a novel role for MR activation in SCD that may exacerbate SCD pathophysiology and clinical complications,” the investigators concluded.
Rivera A, Vega C, Ramos-Rivera A, et al. Blockade of the mineralocorticoid receptor improves markers of human endothelial cell dysfunction and hematological indices in a mouse model of sickle cell disease. FASEB J. Published online July 21, 2023. doi:10.1096/fj.202300671R