Angiotensin II: Rapid Localization in Nuclei of Smooth and Cardiac Muscle

Robertson, Abel L.; Khairallah, Philip A.

doi:10.1126/science.172.3988.1138

Cited by 237 publications

(91 citation statements)

References 2 publications

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“…Although previous reports do not specifically anticipate the localization of Ang receptors on mitochondria, some clues may be gleaned from prior work (5,(26)(27)(28)(29). Early studies indicated that radio-labeled Ang II could be associated with the mitochondria (30), and chronic exposure to Ang II had a significant stimulatory effect on rat mitochondrial growth and proliferation (31) as well as improved coupling of respiration and ATP synthesis in intact mitochondria (27).…”

Section: Discussionmentioning

confidence: 99%

“…Although many studies have focused on the impact of extracellular Ang II and its receptors, type 1 (AT 1 R) and type 2 (AT 2 R), on the cardiovascular system, others have reported that Ang II is also present in the intracellular compartment and can be released upon cell stretch to mediate cellular growth and/or apoptosis (1)(2)(3). Although many of the autocrine effects of this endogenous Ang store are believed to be mediated by plasma membrane Ang receptors, an intracellular RAS acting on nuclear Ang receptors has also been proposed (4,5).…”

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confidence: 99%

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Identification and characterization of a functional mitochondrial angiotensin system

Abadir

Foster²,

Crow

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

245

251

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The renin-angiotensin (Ang) system regulates multiple physiological functions through Ang II type 1 and type 2 receptors. Prior studies suggest an intracellular pool of Ang II that may be released in an autocrine manner upon stretch to activate surface membrane Ang receptors. Alternatively, an intracellular renin-Ang system has been proposed, with a primary focus on nuclear Ang receptors. A mitochondrial Ang system has not been previously described. Here we report that functional Ang II type 2 receptors are present on mitochondrial inner membranes and are colocalized with endogenous Ang. We demonstrate that activation of the mitochondrial Ang system is coupled to mitochondrial nitric oxide production and can modulate respiration. In addition, we present evidence of age-related changes in mitochondrial Ang receptor expression, i.e., increased mitochondrial Ang II type 1 receptor and decreased type 2 receptor density that is reversed by chronic treatment with the Ang II type 1 receptor blocker losartan. The presence of a functional Ang system in human mitochondria provides a foundation for understanding the interaction between mitochondria and chronic disease states and reveals potential therapeutic targets for optimizing mitochondrial function and decreasing chronic disease burden with aging.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Identification and characterization of a functional mitochondrial angiotensin system

Abadir

Foster²,

Crow

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

245

251

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“…Overexpression of AT1Rs is a much more potent stimulus to cardiac remodeling than Ang-II overproduction, suggesting that receptor density may be the limiting factor for Ang-II-related remodeling (35). It has long been known that radiolabeled Ang-II preferentially localizes in the perinuclear regions of cardiomyocytes following intraventricular injection (36). The presence of nuclear Ang-II receptors has been demonstrated in the liver (11,12) and kidneys (37).…”

Section: Discussionmentioning

confidence: 99%

Nuclear-delimited Angiotensin Receptor-mediated Signaling Regulates Cardiomyocyte Gene Expression

Tadevosyan

Maguy

Villeneuve

et al. 2010

Journal of Biological Chemistry

103

117

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Angiotensin-II (Ang-II) from extracardiac sources and intracardiac synthesis regulates cardiac homeostasis, with mitogenic and growth-promoting effects largely due to altered gene expression. Here, we assessed the possibility that angiotensin-1 (AT1R) or angiotensin-2 (AT2R) receptors on the nuclear envelope mediate effects on cardiomyocyte gene expression. Immunoblots of nucleus-enriched fractions from isolated cardiomyocytes indicated the presence of AT1R and AT2R proteins that copurified with the nuclear membrane marker nucleoporin-62 and histone-3, but not markers of plasma (calpactin-I), Golgi (GRP-78), or endoplasmic reticulum (GM130) membranes. Confocal microscopy revealed AT1R and AT2R proteins on nuclear membranes. Microinjected Ang-II preferentially bound to nuclear sites of isolated cardiomyocytes. AT1R and AT2R ligands enhanced de novo RNA synthesis in isolated cardiomyocyte nuclei incubated with [␣-

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“…[14][15][16][17][18][19] The potential role of intracellular Ang II could be traced back to an early study in which radiolabelled Ang II was found in the nuclei of vascular smooth muscle and cardiac cells following systemic administration. 20 However, Re [25][26][27] Haller et al showed that microinjection of Ang II directly into rat vascular smooth muscle cells increased intracellular calcium, which could be blocked by intracellular AT 1 -receptor blockers. 28,29 Sigmund and associates recently provided evidence that an intracellular form of renin plays a functional role in the brain.…”

Section: Introductionmentioning

confidence: 99%

Review: Novel roles of intracrine angiotensin II and signalling mechanisms in kidney cells

Zhuo

2007

J Renin Angiotensin Aldosterone Syst

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Angiotensin II (Ang II) has powerful sodiumretaining, growth-promoting and proinflammatory properties in addition to its physiological role in maintaining body salt and fluid balance and blood pressure homeostasis. Increased circulating and local tissue Ang II is one of the most important factors contributing to the development of sodium and fluid retention, hypertension and target organ damage.The importance of Ang II in the pathogenesis of hypertension and target organ injury is best demonstrated by the effectiveness of angiotensinconverting enzyme (ACE) inhibitors and AT 1 -receptor antagonists in treating hypertension and progressive renal disease including diabetic nephropathy.The detrimental effects of Ang II are mediated primarily by the AT 1 -receptor, while the AT 2 -receptor may oppose the AT 1 -receptor. The classical view of the AT 1 -receptor-mediated effects of Ang II is that the agonist binds its receptors at the cell surface, and following receptor phosphorylation, activates downstream signal transduction pathways and intracellular responses. However, evidence is emerging that binding of Ang II to its cell surface AT 1 -receptors also activates endocytotic (or internalisation) processes that promote trafficking of both the effector and the receptor into intracellular compartments.Whether internalised Ang II has important intracrine and signalling actions is not well understood.The purpose of this article is to review recent advances in Ang II research with focus on the mechanisms underlying high levels of intracellular Ang II in proximal tubule cells and the contribution of receptor-mediated endocytosis of extracellular Ang II. Further attention is devoted to the question whether intracellular and/or internalised Ang II plays a physiological role by activating cytoplasmic or nuclear receptors in proximal tubule cells.This information may aid future development of drugs to prevent and treat Ang II-induced target organ injury in cardiovascular and renal diseases by blocking intracellular and/or nuclear actions of Ang II.

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Angiotensin II: Rapid Localization in Nuclei of Smooth and Cardiac Muscle

Cited by 237 publications

References 2 publications

Identification and characterization of a functional mitochondrial angiotensin system

Identification and characterization of a functional mitochondrial angiotensin system

Nuclear-delimited Angiotensin Receptor-mediated Signaling Regulates Cardiomyocyte Gene Expression

Review: Novel roles of intracrine angiotensin II and signalling mechanisms in kidney cells

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