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 ...

Association between serum vitamin D levels and subclinical coronary atherosclerosis and plaque burden/composition in young adult population

“…In addition, Al Mheid et al [22] reported that 25(OH)D insuffi ciency was associated with increased arterial stiff ness and endothelial dysfunction in a community-based asymptomatic population. Another mechanism may be pancreatic β-cell dysfunction, peripheral tissue resistance to insulin predisposing to diabetes [23], and activation of the renin-angiotensin system predisposing to hypertension [24]. In addition, Oh et al [25].…”

Calcitriol Supplementation Improves Endothelium-Dependent Vasodilation in Rat Hypertensive Renal Injury

“…Although the exact reasons for these diverse results are unclear, they may be attributed to differing ARBs, methods of measuring AngII levels, and the renal disease models used. In addition, vitamin D decreases renin expression [3]. Accordingly, plasma renin activity and AngII levels reduced in the V group.…”

“…Atherosclerotic cardiovascular complications are very common among patients with CKDs, and suppression of the RAS retards the progression of renal dysfunction in various CKDs [1]. Recent findings indicate that vitamin D diminishes renin expression [3]. Thus, vitamin D may exert renoprotective effects through the inhibition of the RAS.…”

Non-classical effects of vitamin D

“…Выявлено, что по-сле использования 2 доз препарата экспрессия ренина снизилась на 35%, а после назначения 5 доз -на 50%. Кроме того, на культурах клеток экспериментально уста-новлено, что кальцитриол непосредственно подавляет транскрипцию гена ренина по VDR-зависимому меха-низму [52]. Таким образом, в этом исследовании авто-ры предоставили данные как in vivo, так и in vitro о том, что витамин D действительно является потенциально не-гативным регулятором РАС.…”