Aldosterone: Essential for Life but Damaging to the Vascular Endothelium

Abstract

The renin angiotensin aldosterone system is a key regulator of blood pressure. Aldosterone is the final effector of this pathway, acting predominantly via mineralocorticoid receptors. Aldosterone facilitates the conservation of sodium and, with it, water and acts as a powerful stimulus for potassium excretion. However, evidence for the pathological impact of excess mineralocorticoid receptor stimulation is increasing. Here, we discussed how in the heart, hyperaldosteronism is associated with fibrosis, cardiac dysfunction, and maladaptive hypertrophy. In the kidney, aldosterone was shown to cause proteinuria and fibrosis and may contribute to the progression of kidney disease. More recently, studies suggested that aldosterone excess damaged endothelial cells. Here, we reviewed how damage to the endothelial glycocalyx may contribute to this process. The endothelial glycocalyx is a heterogenous, negatively charged layer on the luminal surface of cells. Aldosterone exposure alters this layer. The resulting structural changes reduced endothelial reactivity in response to protective shear stress, altered permeability, and increased immune cell trafficking. Finally, we reviewed current therapeutic strategies for limiting endothelial damage and suggested that preventing glycocalyx remodelling in response to aldosterone exposure may provide a novel strategy, free from the serious adverse effect of hyperkalaemia seen in response to mineralocorticoid blockade.

Keywords: aldosterone; endothelium; glycocalyx; mineralocorticoid receptor.

Figure 1

Multiple pathways coordinate and regulate aldosterone signalling. Multiple stimuli result in aldosterone production within the adrenal glands, the role of localized aldosterone production remains unknown. Circulating aldosterone my act on cell surface MR receptors and GPER in addition to the cytosolic MR receptor. The ‘classical’ aldosterone signalling pathway (via cytosolic MR) is protected from cortisol activation by hydroxysteroid dehydrogenase 2 activity. These complex pathways all represent potential future therapeutic targets.

Figure 2

The glomerular filtration barrier. In the representative diagram, (A) the filtrate passes the layers of the filter. Albumin is largely excluded, as indicated by the local albumin concentration on the right. Electron microscopy (B) demonstrates the functional arrangement of cells within the glomerulus [84]. GBM = glomerular basement membrane, GEnC = glomerular endothelial cells, PFP = podocyte foot process.

Figure 3

A suggested mechanism by which aldosterone may affect immune cell transit. In health, repulsion between the negatively charged glycocalyx of white blood cells and the vessel wall limits their interaction. Given the difference in height, the glycocalyx (∼500 nm) shields selectins (∼40 nm). Glycocalyx damage reduces the negative surface charge and allows for electrostatic attraction of white blood cells to the endothelium, which then mediate receptor–ligand interactions, resulting in tethering, rolling, adhesion, and diapedesis.