Impact of Aldosterone on Osteoinductive Signaling and Vascular Calcification

Abstract

Vascular calcification is frequently found already in early stages of chronic kidney disease (CKD) patients and is associated with high cardiovascular risk. The process of vascular calcification is not considered a passive phenomenon but involves, at least in part, phenotypical transformation of vascular smooth muscle cells (VSMCs). Following exposure to excessive extracellular phosphate concentrations, VSMCs undergo a reprogramming into osteo-/chondroblast-like cells. Such ‘vascular osteoinduction' is characterized by expression of osteogenic transcription factors and triggered by increased phosphate concentrations. A key role in this process is assigned to cellular phosphate transporters, most notably the type III sodium-dependent phosphate transporter Pit1. Pit1 expression is stimulated by mineralocorticoid receptor activation. Therefore, aldosterone participates in the phenotypical transformation of VSMCs. In preclinical models, aldosterone antagonism reduces vascular osteoinduction. Patients with CKD suffer from hyperphosphatemia predisposing to vascular osteogenic transformation, potentially further fostered by concomitant hyperaldosteronism. Clearly, additional research is required to define the role of aldosterone in the regulation of osteogenic signaling and the consecutive vascular calcification in CKD, but more generally also other diseases associated with excessive vascular calcification and even in individuals without overt disease.

Mineral bone disorders in chronic kidney disease

“…The activated angiotensin‐II will enhance the production of aldosterone. Phosphate and calcium stimulate the Na‐Pi cotransporter, and aldosterone also contributes to activate the Na‐Pi cotransporter, resulting in increased phosphate entrance into VSMC . In addition, aldosterone accentuates the inflammatory status in part by tumour necrosis factor alpha (TNFα).…”

“…In addition, aldosterone accentuates the inflammatory status in part by tumour necrosis factor alpha (TNFα). Both oxidative/inflammatory status and increased intracellular phosphate levels promote VSMC to transdifferentiate into phenotypic OB cells, which causes the ossification of the vascular wall to progress . As a whole, the calcified vessels have more prominent bone formation characteristic than bone resorption ones.…”

Vascular and inflammatory mineralocorticoid receptors in kidney disease

“…Indeed, nearly 50% of the mortality in CKD is associated with cardiovascular injury. 27,82 Aldosterone synthase expression is augmented in human aortic smooth muscle cells under conditions that favour vascular calcification, including klotho deficiency or excessive phosphate concentrations, likely enhancing aldosterone/MR participation in vascular calcification. The MRA spironolactone prevents vascular calcification in adenine-induced CKD and klotho hypomorphic mice (which display CKD characteristics).…”

On the Pleotropic Actions of Mineralocorticoids

“…Moreover, mineralocorticoids increase vascular stiffness [33,34] and vascular as well as soft tissue calcification [25,35,36], as amplified in a separate contribution to this special issue [37]. Mineralocorticoids influence tissue calcification in part by downregulation of klotho [38,39].…”

“…The cardiovascular disease in mineralocorticoid excess is the result of extracellular volume expansion with hypertension [7,8,41], endothelial stiffness with compromised NO release [26,27,28,29,30], cardiovascular inflammation and fibrosis [43,57,117,118] as well as calcification with enhanced vascular stiffness [35,36,37]. Moreover, vascular events may result from enhanced Ca 2+ entry into blood platelets [69] with enhanced degranulation, aggregation and adhesion [68] and eventually acute thrombotic occlusion following atherosclerotic plaque rupture [82,119] and ischemic cardiovascular events such as myocardial infarction or ischemic stroke [120].…”