Nuclear Hormone Receptors as Regulators of the Renin-Angiotensin-Aldosterone System

Harst

Laboratory Investigation

et al. 2010

Self Cite

Liver X receptor (LXR)-a is a pivotal player in reverse cholesterol metabolism. Recently, LXR-a was implicated as an immediate regulator of renin expression in a cAMP-responsive manner. To determine whether long-term LXR-a activation affects activation of the renal and cardiac renin-angiotensin-aldosterone system (RAAS), we treated mice with T0901317 (T09, a specific synthetic LXR agonist) in combination with the RAAS inducer isoproterenol (ISO). LXR-a-deficient (LXR-a À/À ) and wild-type (WT) C57Bl/6J mice were treated with ISO, T09 or both for 7 days. Low-dose ISO treatment, not associated with an increase in blood pressure, caused an increase in renal renin mRNA, renin protein and ACE protein in WT mice. WT mice treated with both ISO and T09 had decreased renal renin, ACE and AT 1 R mRNA expression compared with mice treated with ISO only. Cardiac ACE mRNA expression was also reduced in the hearts of WT mice treated with ISO and T09 compared with those treated with ISO alone. The transcriptional changes of renin, ACE and AT 1 R were mostly absent in mice deficient for LXR-a, suggesting that these effects are importantly conferred through LXR-a. In conclusion, LXR-a activation blunts ISO-induced increases in mRNA expression of renin, AT 1 R and ACE in the heart and kidney. These findings suggest a role for LXR-a in RAAS regulation.

Section: Discussionmentioning

confidence: 92%

Activation of liver X receptor-α reduces activation of the renal and cardiac renin–angiotensin–aldosterone system

Harst

Laboratory Investigation

et al. 2010

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“…strongly suppressed by the VDR [71], as well as by other nuclear receptors [72]. This suppression is caused by blockade of the cyclic AMP response element in the renin gene promoter [73].…”

Section: Cdkn1a (P21)mentioning

confidence: 99%

Vitamin D Deficiency: Universal Risk Factor for Multifactorial Diseases?

Borst¹,

Boer²,

Stolk³

et al. 2011

CDT

Self Cite

In the Western world, the majority of morbidity and mortality are caused by multifactorial diseases. Some risk factors are related to more than one type of disease. These so-called universal risk factors are highly relevant to the population, as reduction of universal risk factors may reduce the prevalence of several types of multifactorial disease simultaneously. Vitamin D deficiency is traditionally seen as an etiological factor in bone disorders such as rickets and osteomalacia. Recent studies also suggest a role for vitamin D deficiency in multifactorial disorders, including progressive renal function loss and cardiovascular disease; it is also a risk factor for frailty. The potentially pleiotropic effects of vitamin D analogues support the hypothesis that vitamin D deficiency is a universal risk factor. Here we review molecular actions of the vitamin D receptor (VDR), to identify mechanisms and pathways for vitamin D deficiency as a universal risk factor. To identify genes directly regulated by the VDR, we searched for genes containing vitamin D response elements (VDREs). A further refinement was made by selecting only VDRE-containing genes with documented modulation by VDR analogues in vivo. Our search yielded a limited number of factors possibly related to pleiotropic effects of vitamin D, including growth factors, hormones, inflammatory factors and factors related to calcium homeostasis. Results from observational, intervention and mechanistic studies indicate that vitamin D is a universal risk factor involved in diverse multifactorial conditions. Further exploration of the multifaceted actions of vitamin D may pave the way for disease-overriding intervention strategies.

“…Like PPARα, PPARγ was also recently reported to play a stimulatory role on expression of the renin-angiotensinaldosterone system (Todorov et al, 2007;Weatherford et al, 2007). Therefore, like the fibrates (PPARα agonists), the thiazolidinediones (PPARγ agonists) are also now under scrutiny for possible blood pressure-elevating effects via increased renin-angiotensin-aldosterone activity (Todorov et al, 2007;Weatherford et al, 2007;Kuipers et al, 2008). However, all efforts thus far to uncover evidence of thiazolidinedione-induced pressure elevations have failed.…”

Section: Effects Of Gemfibrozil On K Ne and Avp Induced Contractionsmentioning

confidence: 99%

“…Thus, an important question is now being raised, i.e. whether fibrates by stimulating PPARα will aggravate related forms of hypertension in humans (Yagil and Yagil, 2007;Kuipers et al, 2008). This is also important because hypertension is so highly prevalent among dyslipidemic patients (particularly those with hypertriglyceridemias) (Criqui et al, 1986;Assmann and Schulte, 1987).…”

Section: Introductionmentioning

confidence: 99%

Evidence of direct smooth muscle relaxant effects of the fibrate gemfibrozil

Phelps

Peuler

2010

J. Smooth Muscle Res.

Fibrates are commonly employed to treat abnormal lipid metabolism via their unique ability to stimulate peroxisome proliferator-activated receptor alpha (PPARα). Interestingly, they also decrease systemic arterial pressure, despite recent evidence that PPARα may contribute to expression of renin and related hypertension. Yet, mechanisms responsible for their potential antihypertensive activity remain unresolved. Rapid decreases in arterial pressure following bolus intravenous injections of bezafibrate strongly suggest they may relax arterial smooth muscle directly. But since bezafibrate is highly susceptible to photodegradation in aqueous media, it has never been critically tested for this possibility in vitro with isolated arterial smooth muscle preparations. Accordingly, we tested gemfibrozil which is resistant to photodegradation. We examined it over a therapeutically-relevant range (50-400 μM) for both acute and delayed relaxant effects on contractions of the isolated rat tail artery; contractions induced by either depolarizing its smooth muscle cell membranes with high potassium or stimulating its membrane-bound receptors with norepinephrine and arginine-vasopressin. We also examined these same gemfibrozil levels for effects on spontaneously-occurring phasic rhythmic contractile activity, typically not seen in arteries under in vitro conditions but commonly exhibited by smooth muscle of uterus, duodenum and bladder. We found that gemfibrozil significantly relaxed all induced forms of contraction in the rat tail artery, acutely at the higher test levels and after a delay of a few hours at the lower test levels. The highest test level of gemfibrozil (400 μM) also completely abolished spontaneously-occurring contractile activity of the isolated uterus and duodenum and markedly suppressed it in the bladder. This is the first evidence that a fibrate drug can directly relax smooth muscle contractions, either induced by various contractile agents or spontaneously-occurring. These findings are particularly relevant to both the recently renewed concern over the impact of fibrates on hypertension and a new understanding of their gastrointestinal side effects.