Recent Updates on the Proximal Tubule Renin-Angiotensin System in Angiotensin II-Dependent Hypertension

Li, Xiao C.; Zhuo, Jia L.

doi:10.1007/s11906-016-0668-z

Cited by 29 publications

(28 citation statements)

References 179 publications

(276 reference statements)

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“…In particular, adenosine, Ang II, NO and

O_{2}^{-}

are important modulators of arteriolar tone and reactivity, as well as tubular reabsorption (see ref. ). Numerous studies have demonstrated that oxidative stress and subsequent NO deficiency in the kidney are critically associated with development of hypertension and increased risk of adverse cardiovascular complications (see ref.…”

Section: Organ Systems Involved In the Blood Pressure Reduction By Inmentioning

confidence: 97%

Mechanisms underlying blood pressure reduction by dietary inorganic nitrate

2018

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Nitric oxide (NO) importantly contributes to cardiovascular homeostasis by regulating blood flow and maintaining endothelial integrity. Conversely, reduced NO bioavailability is a central feature during natural ageing and in many cardiovascular disorders, including hypertension. The inorganic anions nitrate and nitrite are endogenously formed after oxidation of NO synthase (NOS)-derived NO and are also present in our daily diet. Knowledge accumulated over the past two decades has demonstrated that these anions can be recycled back to NO and other bioactive nitrogen oxides via serial reductions that involve oral commensal bacteria and various enzymatic systems. Intake of inorganic nitrate, which is predominantly found in green leafy vegetables and beets, has a variety of favourable cardiovascular effects. As hypertension is a major risk factor of morbidity and mortality worldwide, much attention has been paid to the blood pressure reducing effect of inorganic nitrate. Here, we describe how dietary nitrate, via stimulation of the nitrate-nitrite-NO pathway, affects various organ systems and discuss underlying mechanisms that may contribute to the observed blood pressure-lowering effect.

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“…In particular, adenosine, Ang II, NO and

O_{2}^{-}

Section: Organ Systems Involved In the Blood Pressure Reduction By Inmentioning

confidence: 97%

Mechanisms underlying blood pressure reduction by dietary inorganic nitrate

2018

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“…Multiple Ga q coupled receptors have been used to probe RGS2 function in vitro such as M1 or M3 muscarinic receptors (Bodenstein et al, 2007;Gu et al, 2007Gu et al, , 2008 or the vasopressin receptor (Osei-Owusu et al, 2007). In this study, we chose the angiotensin II receptor because of its relevance in systematic regulation of vascular function and blood pressure (de Kloet et al, 2015;Cameron et al, 2016;Li and Zhuo, 2016). Moreover, RGS2 has been proposed to serve as a selective and potent regulator of AT1R due to interaction through its amino terminal domains (Heximer et al, 2003;Hercule et al, 2007;Matsuzaki et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Human Missense Mutations in Regulator of G Protein Signaling 2 Affect the Protein Function Through Multiple Mechanisms

2017

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Regulator of G protein signaling 2 (RGS2) plays a significant role in alleviating vascular contraction and promoting vascular relaxation due to its GTPase accelerating protein activity toward Gq. Mice lacking RGS2 display a hypertensive phenotype, and several RGS2 missense mutations have been found predominantly in hypertensive human subjects. However, the mechanisms whereby these mutations could impact blood pressure is unknown. Here, we selected 16 rare, missense mutations in RGS2 identified in various human exome sequencing projects and evaluated their ability to inhibit intracellular calcium release mediated by angiotensin II receptor type 1 (AT1R). Four of them had reduced function and were further investigated to elucidate underlying mechanisms. Low protein expression, protein mislocalization, and reduced G protein binding were identified as likely mechanisms of the malfunctioning mutants. The Q2L mutant had 50% lower RGS2 than wild-type (WT) protein detected by Western blot. Confocal microscopy demonstrated that R44H and D40Y had impaired plasma membrane targeting; only 46% and 35% of those proteins translocated to the plasma membrane when coexpressed with G Q209L compared with 67% for WT RGS2. The R188H mutant had a significant reduction in G binding affinity (10-fold increase in compared with WT RGS2 in a flow cytometry competition binding assay). This study provides functional data for 16 human RGS2 missense variants on their effects on AT1R-mediated calcium mobilization and provides molecular understanding of those variants with functional loss in vitro. These molecular behaviors can provide insight to inform antihypertensive therapeutics in individuals with variants having reduced function.

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“…Such sophisticated autoregulation is mediated by the myogenic response and the tubuloglomerular feedback (TGF), which mainly exert their effect via modulation of afferent arteriolar tone . In addition, several hormones and endogenous substances can modulate renal autoregulation and preglomerular resistance , where adenosine, Ang II, NO and

O_{2}^{-}

have been demonstrated to be of particular importance . Abnormal renal autoregulation and altered fluid and electrolyte handling along the nephron may contribute to the development of hypertension, which in turn can induce progressive renal injuries .…”

Section: Kidneys and Renal Autoregulationmentioning

confidence: 99%

Therapeutic value of stimulating the nitrate‐nitrite‐nitric oxide pathway to attenuate oxidative stress and restore nitric oxide bioavailability in cardiorenal disease

Carlström

Montenegro

2018

J Intern Med

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Cardiovascular disorders including hypertension and associated renal disease are major health problems affecting more than 1.5 billion people worldwide. Apart from nonmodifiable factors such as ageing, family history and gender, both sedentary lifestyle and unhealthy dietary habits are considered as major risk factors. The disorders are interrelated suggesting common pathological pathways. Mechanistically, oxidative stress and compromised function of the nitric oxide synthase (NOS) system leading to endothelial dysfunction and reduction in nitric oxide (NO) bioavailability have been widely implicated and associated with development and progression of disease. New strategies that correct this redox imbalance and increase NO bioactivity may have major clinical implications. The inorganic anions, nitrate and nitrite, are endogenously formed by oxidization of NOS-derived NO, but there are also high amounts of nitrate in our daily diet. In this regard, accumulated evidence over the past two decades demonstrates that these anions can be recycled back to NO and other bioactive nitrogen oxides, thus offering an attractive alternative strategy for therapeutic exploitation. In this review, we describe how dietary stimulation of the nitrate-nitrite-NO pathway affects cardiovascular and renal functions in health and disease via modulation of oxidative stress and NO bioavailability. Clinical studies addressing potential effects on the renal system are still limited, but blood pressure-lowering effects of nitrate supplementation have been demonstrated in healthy and hypertensive subjects as well as in patients with chronic kidney disease. However, larger clinical studies are warranted to reveal whether chronic nitrate treatment can slow-down the progression of cardiorenal disease and associated complications.

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Recent Updates on the Proximal Tubule Renin-Angiotensin System in Angiotensin II-Dependent Hypertension

Cited by 29 publications

References 179 publications

Mechanisms underlying blood pressure reduction by dietary inorganic nitrate

Mechanisms underlying blood pressure reduction by dietary inorganic nitrate

Human Missense Mutations in Regulator of G Protein Signaling 2 Affect the Protein Function Through Multiple Mechanisms

Therapeutic value of stimulating the nitrate‐nitrite‐nitric oxide pathway to attenuate oxidative stress and restore nitric oxide bioavailability in cardiorenal disease

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