A functional angiotensin II receptor-GFP fusion protein: evidence for agonist-dependent nuclear translocation

Chen, Ruihua; Mukhin, Y.; Garnovskaya, Maria N.; Thielen, Thomas E.; Iijima, Yoshihiro; Huang, Cancan; Raymond, John R.; Ullian, Michael E.; Paul, Richard V.

doi:10.1152/ajprenal.2000.279.3.f440

Cited by 91 publications

(73 citation statements)

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“…nuclei of epithelial cells or isolated from the kidney, [97][98][99][100] there is no study specifically designed to localise internalised Ang II and AT 1 -receptors in proximal tubule cells in vitro and in vivo. It would be interesting to use state-of-the-art electron microscopic autoradiography and immunohistochemistry to localise internalised Ang II and AT 1 -receptors, focusing mainly in proximal tubule cells ex vivo, and use confocal and fluorescence microscopy for similar studies in cultured proximal tubule cells in vitro.…”

Section: O P Y R I G H T J R a A S L I M I T E D R E P R O D U C T mentioning

confidence: 99%

“…Intracellular kinases activated by Ang II include extracellular signal-regulated protein kinase(s) (ERKs) 63,70,117,122 JAK-STAT signalling 117,123,124 and calcineurin phosphatase. 126,127 Internalised Ang II may also be translocated to the nucleus, 20,97,99,110 where it may activate nuclear calcium 28,29,45 and stimulate transcription of NHE-3 and pro-inflammatory cytokines and growth factors. 20,47,69,97,111,128 Recent studies indicate that Ang II activates nuclear transcription factor NF-κB and activator protein-1 (AP-1) in the kidney, leading to longlasting inflammatory and growth-promoting effects.…”

Section: O P Y R I G H T J R a A S L I M I T E D R E P R O D U C T mentioning

confidence: 99%

“…126,127 Internalised Ang II may also be translocated to the nucleus, 20,97,99,110 where it may activate nuclear calcium 28,29,45 and stimulate transcription of NHE-3 and pro-inflammatory cytokines and growth factors. 20,47,69,97,111,128 Recent studies indicate that Ang II activates nuclear transcription factor NF-κB and activator protein-1 (AP-1) in the kidney, leading to longlasting inflammatory and growth-promoting effects. 47,48,112,129,130 NF-κB is an important transcription factor in inflammatory diseases, and activation of NF-κB by Ang II stimulates transcription of many sodium transporters, cytokines and chemokines, including angiotensinogen, monocyte chemoattractant peptide-1 (MCP-1), TGFβ, and RANTES (regulated on activation normal T cell expressed and secreted).…”

Section: O P Y R I G H T J R a A S L I M I T E D R E P R O D U C T mentioning

confidence: 99%

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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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Section: O P Y R I G H T J R a A S L I M I T E D R E P R O D U C T mentioning

confidence: 99%

Section: O P Y R I G H T J R a A S L I M I T E D R E P R O D U C T mentioning

confidence: 99%

Section: O P Y R I G H T J R a A S L I M I T E D R E P R O D U C T mentioning

confidence: 99%

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

Zhuo

2007

J Renin Angiotensin Aldosterone Syst

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“…7 These observations again raise the possibility that complete intracellular renin-angiotensin systems exist in some cells. [13][14][15][32][33][34][35][36] These intracrine renin-angiotensin systems (iRAS) could offer a new therapeutic target, given the differential ability of various inhibitors to act at intracellular sites. Parenthetically, regulatory loops linking the iRAS components angiotensinogen with p53 and renin with nucleolin mirror the regulatory relations of other intracrines with p53 and nucleolin.…”

Section: Intracrine Prorenin/reninmentioning

confidence: 99%

Intracellular Renin and the Nature of Intracrine Enzymes

Ré

2003

Hypertension

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Abstract-Recently, the binding of renin and prorenin to cellular receptors with the subsequent generation of second messengers and the production of physiological effects has been demonstrated. In addition, the internalization of prorenin by target cells has been associated with increased cellular synthesis of angiotensin and cardiac pathology. Also, a renin transcript lacking the sequences encoding a secretory signal has been reported, and this transcript appears to produce a renin that acts in the cell that synthesized it. Some years ago, we coined the term intracrine for a peptide hormone or factor that acts in the intracellular space either after internalization or retention in its cell of synthesis. Thus defined, a wide variety of peptides display intracrine functionality, including hormones, growth factors, transcription factors, and enzymes. For example, considerable evidence indicates that angiotensin II is an intracrine. Also, general principles of intracrine functionality have been developed. Thus, recent evidence demonstrates that the prorenin/renin molecule is an intracrine enzyme. Here, the actions of intracrine enzymes (angiogenin, phosphoglucose isomerase, phospholipase A2, granzyme A and B, thioredoxin, platelet-derived endothelial growth factor, and serine protease inhibitors) are reviewed. Key Words: renin Ⅲ platelet-derived growth factor Ⅲ enzymes Ⅲ angiotensin II Ⅲ phospholipases R enin gene expression leads to the synthesis of prorenin in the juxtaglomerular cells of the kidney, activation and secretion of renin by these cells, the generation of angiotensin I by renin enzymatic activity, and the subsequent generation of angiotensin II either in the plasma or tissues. However, renin, angiotensin I, and angiotensin II can also be taken up by tissues with subsequent enzymatic conversions occurring locally. Moreover, there is considerable evidence, both in animal models and in humans, in favor of the local synthesis of each of the components of the renin-angiotensin system (RAS) in various tissues leading to locally determined angiotensin generation. 1 In addition to evidence indicating local synthesis and uptake in tissues of RAS components, there is growing evidence to indicate the uptake and synthesis of components of the RAS by individual cells, thereby suggesting a new arena for the action of this physiological system. 2 Important among these new observations are studies demonstrating that (1) prorenin and renin can bind to specific cellular receptors with the generation of physiological effects, (2) prorenin, and to a lesser extent, renin, can be internalized by cells whereupon angiotensin II is produced, and (3) there exists a renin transcript in some cells that encodes a renin that is expected to be synthesized as an active, as opposed to a prorenin, and that is expected to remain in the cell because it lacks the sequence encoding the secretory signal piece (renin exon 1A). 2-13 These observations not only reveal prorenin and renin to be hormones in their own right, they suggest that pro...

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“…Moreover, electron microscopic immunohistochemical techniques were used to demonstrate angiotensin II immunoreactivity located in association with the euchromatin of cerebellar neurons, hepatocytes, and adrenal cells from normal animals (13). Also confocal microscopy studies demonstrated that functional fluorescent-labeled At-1 receptors traffic to the nuclear interior upon agonist binding (7). In addition, the direct introduction of angiotensin or renin into the intracellular space produced alterations in calcium flux and conductance in cardiac myocytes (11,14,47).…”

Section: Intracrine Renin Angiotensin Systemmentioning

confidence: 99%

Implications of intracrine hormone action for physiology and medicine

Ré

2003

American Journal of Physiology-Heart and Circulatory Physiology

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A functional angiotensin II receptor-GFP fusion protein: evidence for agonist-dependent nuclear translocation

Cited by 91 publications

References 32 publications

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

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

Intracellular Renin and the Nature of Intracrine Enzymes

Implications of intracrine hormone action for physiology and medicine

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