The renin-angiotensin-aldosterone system and calcium-regulatory hormones

Abstract

There is increasing evidence of a clinically relevant interplay between the renin-angiotensin-aldosterone system and calcium-regulatory systems. Classically, the former is considered a key regulator of sodium and volume homeostasis, while the latter is most often associated with skeletal health. However, emerging evidence suggests an overlap in regulatory control. Hyperaldosteronism and hyperparathyroidism represent pathophysiologic conditions that may contribute to or perpetuate each other; aldosterone regulates parathyroid hormone and associates with adverse skeletal complications, and parathyroid hormone regulates aldosterone and associates with adverse cardiovascular complications. As dysregulation in both systems is linked to poor cardiovascular and skeletal health, it is increasingly important to fully characterize how they interact to more precisely understand their impact on human health and potential therapies to modulate these interactions. This review describes the known clinical interactions between these two systems including observational and interventional studies. Specifically, we review studies describing the inhibition of renin activity by calcium and vitamin D, and a potentially bidirectional and stimulatory relationship between aldosterone and parathyroid hormone. Deciphering these relationships might clarify variability in outcomes research, inform the design of future intervention studies and provide insight into the results of prior and ongoing intervention studies. However, before these opportunities can be addressed, more effort must be placed on shifting observational data to the proof of concept phase. This will require reallocation of resources to conduct interventional studies and secure the necessary talent.

Interactions between the renin-angiotensin-aldosterone system and calcium-regulatory hormones

The 1,25(OH)₂D-VDR complex, and calcium ion, can decrease plasma renin activity either by decreases renin expression or decreasing renin secretion, respectively. Some evidence has shown that PTH may directly increase renin secretion in the acute setting. Aldosterone and angiotensin II stimulate the secretion of PTH via the MR and AT1R; the former with chronic exposure whereas the latter in the acute setting. PTH, in turn, has been implicated as an aldosterone secretagogue via interactions with the PTH-R in the adrenal zona glomerulosa. 25(OH)D=25-hydroxyvitamin D 1,25(OH)₂D=1,25-dihydroxyvitamin D VDR=vitamin D receptor PTH=parathyroid hormone Ca²⁺=calcium cation CaSR=calcium sensing receptor MR=mineralocorticoid receptor AT1R=angiotensin receptor type 1 ACE=angiotensin converting enzyme