1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system

Abstract

IntroductionThe renin-angiotensin system is a regulatory cascade that plays an essential role in the regulation of blood pressure, electrolyte, and volume homeostasis. The first and rate-limiting component of this cascade is renin, a protease synthesized and secreted predominantly by the juxtaglomerular (JG) apparatus in the nephron. Renin cleaves angiotensin I (Ang I) from liver-derived angiotensinogen, which is then converted to Ang II by the angiotensin-converting enzyme. Ang II, through binding to its receptors, exerts diverse actions that affect the electrolyte, volume, and blood pressure homeostasis (1). Inappropriate stimulation of the renin-angiotensin system has been associated with hypertension, heart attack, and stroke.The renin-producing granulated cells are mainly located in the afferent glomerular arterioles in the kidney (2). It is well established that renin secretion is regulated by renal perfusion pressure, renal sympathetic nerve activity, and tubular sodium load (1, 2). Renin secretion is stimulated by factors such as prostaglandins, NO, and adrenomedullin, and inhibited by other factors, including Ang II (feedback), endothelin, vasopressin, and adenosine (1, 2). Stimulation of renin secretion is often mediated by an increase in intracellular cAMP and is accompanied by increases in renin gene transcription (3). In the renin gene promoter, several cAMP response elements have been identified. Recently, steroid hormone receptors LXRα and RAR/RXR complex, transcriptional factors CREB/CREM and USF1/USF2, and HOX gene family members have been found to be involved in the activation of murine renin gene transcription (4-7).Vitamin D is a primary regulator of calcium homeostasis. Genetic inactivation of either the vitamin D receptor (VDR), a member of the nuclear receptor superfamily that mediates the action of 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], or 25-hydroxyvitamin D 3 1α-hydroxylase, the rate-limiting enzyme for the biosynthesis of 1,25(OH) 2 D 3 , results in impaired calcium homeostasis, leading to hypocalcemia, secondary hyperparathyroidism, and rickets (8-11). However, the wide tissue distribution of VDR suggests that the vitamin D endocrine system has additional physiological functions beyond calcium homeostasis. Indeed, vitamin D and VDR have been shown to play important roles in the immune system, cardiovascular system, reproductive system, and hair growth. Inappropriate activation of the renin-angiotensin system, which plays a central role in the regulation of blood pressure, electrolyte, and volume homeostasis, may represent a major risk factor for hypertension, heart attack, and stroke. Mounting evidence from clinical studies has demonstrated an inverse relationship between circulating vitamin D levels and the blood pressure and/or plasma renin activity, but the mechanism is not understood. We show here that renin expression and plasma angiotensin II production were increased severalfold in vitamin D receptor-null (VDR-null) mice, leading to hypertension, cardiac hypertrophy, and ...

Mendelian Randomization Studies Do Not Support a Role for Vitamin D in Coronary Artery Disease

“…14 Other mechanistic explanations have been proposed, including endothelial dysfunction from the lack of adequate vitamin D, vascular compliance impairment because of smooth muscle changes, enhanced inflammation, effects related to high levels of PTH, or the renin-angiotensin system. [15][16][17] Finally, some studies have suggested that vitamin D supplementation could lower vascular risk by improving glucose tolerance or by inhibiting inflammatory components in the metabolic syndrome. [18][19][20] Recent meta-analyses of observational studies have reported, on balance, a significant relationship between 25OHD levels and composite cardiovascular events.…”

Vitamin D insufficiency is associated with coronary artery tortuosity

“…Recent clinical studies have associated low levels of 25-OH VD with hypertension, coronary artery calcification, and cardiovascular diseases such as myocardial infarction, acute stroke, congestive heart failure, and diabetes mellitus [6][7][8][9]. The mechanisms underlying the role of VD in the prevention of cardiovascular disease are not known; however, they may involve diverse physiological actions on the vascular wall, including reduction of smooth muscle cell proliferation, reduction of secretion of the pro-inflammatory cytokines interleukin-6 and tumour necrosis factor-alpha by macrophages, and increased secretion of the anti-inflammatory cytokine interleukin-10, all acting to reduce vascular inflammation [10,11]. Given its relationship with cardiovascular disease, VD insufficiency may be associated with CT.…”

“…Thus, degeneration of elastin in the arterial wall may lead to aneurysmal dilatation and the de- [22,23]. A recent trial has shown its participation in regulating the expression of many proteins with vascular action, such as vascular endothelial growth factor, type 9 metalloproteinase, myosin, elastin, type 1 collagen, and gamma-carboxyglutamic acid, the latter a protein that protects the vessel against parietal calcification, and also in the suppression of pro-inflammatory cytokines, including interleukin-6 and tumour necrosis factor-alpha in vitro and in vivo [22][23][24]. Moreover, VD suppresses degeneration of elastin in the arterial wall [24].…”

“…Postulated mechanisms for these presumed cardiovascular effects include endothelial dysfunction, inflammation, reduced vessel compliance, detrimental effects via bone proteins such as osteoprotegerin, as well as dysregulation of the renin-angiotensin system and arterial wall calcification because of increased parathyroid hormone levels [10,11]. Additionally, VD effectively preserved the structure of elastic fibres and the ratio of elastic fibres to collagen fibres in the artery media [12].…”

Plasma 25-Hydroxyvitamin D and Severe Pre-Eclampsia in a Population With Profound Vitamin D Deficiency

“…It has immune regulatory, anti-inflammatory, and antihypertensive effects (3). Preeclampsia is a major health problem affecting 2% -8% of pregnancies (4) and the pathogenesis of pre-eclampsia includes a number of processes that may be affected by vitamin D, including inflammation, immune dysfunction, hypertension, and abnormal placenta implantation (5)(6)(7)(8). Vitamin D deficiency has been hypothesized to be linked to the development of pre-eclampsia, but the results of studies on the matter have been inconsistent.…”