Blockade of the mineralocorticoid receptor improves markers of human endothelial cell dysfunction and hematological indices in a mouse model of sickle cell disease

• Published in: The FASEB journal Vol. 37; no. 8; p. e23092
• Main Authors: Rivera, Alicia, Vega, Christopher, Ramos-Rivera, Arelys, Maldonado, Enrique R, Prado, Gregory N, Karnes, Hope E, Fesko, Yuri A, Snyder, L Michael, Alper, Seth L, Romero, Jose R
• Format: Journal Article
• Language: English
• Published: United States 01.08.2023
• Subjects: Aldosterone - metabolism; Anemia, Sickle Cell - drug therapy; Anemia, Sickle Cell - genetics; Animals; Disease Models, Animal; Endothelial Cells - metabolism; Endothelin-1 - metabolism; Humans; Inflammation - metabolism; Mice; Mice, Transgenic; Mineralocorticoid Receptor Antagonists - pharmacology; Receptors, Mineralocorticoid - genetics; Receptors, Mineralocorticoid - metabolism; Vascular Diseases - metabolism; mineralocorticoid receptor; endothelin-1; eplerenone; protein disulfide isomerase; sickle cell disease
• ISSN: 1530-6860
• DOI: 10.1096/fj.202300671R

Increased endothelin-1 (ET-1) levels in patients with sickle cell disease (SCD) and transgenic mouse models of SCD contribute to disordered hematological, vascular, and inflammatory responses. Mineralocorticoid receptor (MR) activation by aldosterone, a critical component of the Renin-Angiotensin-Aldosterone-System, modulates inflammation and vascular reactivity, partly through increased ET-1 expression. However, the role of MR in SCD remains unclear. We hypothesized that MR blockade in transgenic SCD mice would reduce ET-1 levels, improve hematological parameters, and reduce inflammation. Berkeley SCD (BERK) mice, a model of severe SCD, were randomized to either sickle standard chow or chow containing the MR antagonist (MRA), eplerenone (156 mg/Kg), for 14 days. We found that MRA treatment reduced ET-1 plasma levels (p = .04), improved red cell density gradient profile (D ; p < .002), and increased mean corpuscular volume in both erythrocytes (p < .02) and reticulocytes (p < .024). MRA treatment also reduced the activity of the erythroid intermediate-conductance Ca -activated K channel - K 3.1 (Gardos channel, KCNN4), reduced cardiac levels of mRNAs encoding ET-1, Tumor Necrosis Factor Receptor-1, and protein disulfide isomerase (PDI) (p < .01), and decreased plasma PDI and myeloperoxidase activity. Aldosterone (10  M for 24 h in vitro) also increased PDI mRNA levels (p < .01) and activity (p < .003) in EA.hy926 human endothelial cells, in a manner blocked by pre-incubation with the MRA canrenoic acid (1 μM; p < .001). Our results suggest a novel role for MR activation in SCD that may exacerbate SCD pathophysiology and clinical complications.