The intracellular renin–angiotensin system: a new paradigm

Kumar, Rajesh; Singh, Vivek P.; Baker, Kenneth M.

doi:10.1016/j.tem.2007.05.001

Cited by 120 publications

(128 citation statements)

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“…calcium imaging; cytosolic calcium concentration; endoplasmic reticulum; microinjection ANGIOTENSIN II is an eight amino acid peptide that exerts its actions by activation of G protein-coupled receptors, namely AT 1 and AT 2 receptors. Increasing evidence suggests that angiotensin II acts not only as an endocrine/paracrine factor, but also as an autacoid or intracrine peptide, with the ability to signal from within the cell, without stimulating plasma membrane receptors (21,38). We previously reported that intracellular administration of angiotensin II via liposomes increases contractility of rat aorta via activation of intracellular receptors (7).…”

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confidence: 96%

“…The intracellular angiotensin II can result either via uptake from the interstitium or by intracellular synthesis. In the latter case, intracellular renin converts angiotensinogen to angiotensin I, which is further converted to the active angiotensin II by chymase or by the angiotensin-converting enzyme, both of which are present intracellularly (21). The intracellular reninangiotensin system has been identified in the heart (11), kidney (18,19,34,48), and uterus (37).…”

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Intracellular angiotensin II activates rat myometrium

Deliu

Tica

Motoc

et al. 2011

American Journal of Physiology-Cell Physiology

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Deliu E, Tica AA, Motoc D, Brailoiu GC, Brailoiu E. Intracellular angiotensin II activates rat myometrium. Am J Physiol Cell Physiol 301: C559 -C565, 2011. First published May 22, 2011; doi:10.1152/ajpcell.00123.2011.-Angiotensin II is a modulator of myometrial activity; both AT1 and AT2 receptors are expressed in myometrium. Since in other tissues angiotensin II has been reported to activate intracellular receptors, we assessed the effects of intracellular administration of angiotensin II via microinjection on myometrium, using calcium imaging. Intracellular injection of angiotensin II increased cytosolic Ca 2ϩ concentration ([Ca 2ϩ ]i) in myometrial cells in a dose-dependent manner. The effect was abolished by the AT 1 receptor antagonist losartan but not by the AT2 receptor antagonist PD-123319. Disruption of the endo-lysosomal system, but not that of Golgi apparatus, prevented the angiotensin II-induced increase in [Ca 2ϩ ]i. Blockade of AT1 receptor internalization had no effect, whereas blockade of microautophagy abolished the increase in [Ca 2ϩ ]i produced by intracellular injection of angiotensin II; this indicates that microautophagy is a critical step in transporting the peptide into the endo-lysosomes lumenum. The response to angiotensin II was slightly reduced in Ca 2ϩ -free saline, indicating a major involvement of Ca 2ϩ release from internal stores. Blockade of inositol 1,4,5-trisphosphate (IP 3) receptors with heparin and xestospongin C or inhibition of phospholipase C (PLC) with U-73122 abolished the response to angiotensin II, supporting the involvement of PLC-IP 3 pathway. Angiotensin II-induced increase in [Ca 2ϩ ]i was slightly reduced by antagonism of ryanodine receptors. Taken together, our results indicate for the first time that in myometrial cells, intracellular angiotensin II activates AT 1-like receptors on lysosomes and activates PLC-IP 3-dependent Ca 2ϩ release from endoplasmic reticulum; the response is further augmented by a Ca 2ϩ -induced Ca 2ϩ release mechanism via ryanodine receptors activation. calcium imaging; cytosolic calcium concentration; endoplasmic reticulum; microinjection ANGIOTENSIN II is an eight amino acid peptide that exerts its actions by activation of G protein-coupled receptors, namely AT 1 and AT 2 receptors. Increasing evidence suggests that angiotensin II acts not only as an endocrine/paracrine factor, but also as an autacoid or intracrine peptide, with the ability to signal from within the cell, without stimulating plasma membrane receptors (21, 38). We previously reported that intracellular administration of angiotensin II via liposomes increases contractility of rat aorta via activation of intracellular receptors (7). Similarly, microinjection of angiotensin II increases cytosolic Ca 2ϩ concentration ([Ca 2ϩ ] i ) in vascular smooth muscle cells (13, 16) or kidney proximal tubule cells (49). The intracellular angiotensin II can result either via uptake from the interstitium or by intracellular synthesis. In the latter case, intracellular renin conver...

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confidence: 96%

mentioning

confidence: 99%

Intracellular angiotensin II activates rat myometrium

Deliu

Tica

Motoc

et al. 2011

American Journal of Physiology-Cell Physiology

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“…11,12 "We believe that intracellular angiotensin II is the main driver of chronic conditions, such as heart failure, at least under diabetogenic conditions. It may thus be necessary to block production of intracellular angiotensin II to prevent downstream expression of genes that can trigger cardiac hypertrophy and fibrosis," said Kumar, who is an assistant professor of internal medicine.…”

Section: Inside Attackmentioning

confidence: 99%

ACE in the hole

Fulmer¹

2010

Science-Business eXchange

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American and Japanese researchers may have found a way to boost the efficacy of marketed angiotensin-converting enzyme inhibitors by combining them with inhibitors of chymase, 1 a protease that is abundant in cardiac tissue. The researchers now want to partner with a company to test the dual inhibitor strategy in a clinical trial to treat hypertension.Angiotensin-converting enzyme (ACE) inhibitors prevent ACE from converting angiotensin I to angiotensin II. By doing so, the molecules counteract multiple downstream effects of excessive angiotensin II, including high blood pressure as well as cardiac hypertrophy and fibrosis that can lead to heart failure.However, chronic use of the drugs can lead to a phenomenon known as ACE inhibitor escape, in which angiotensin II levels do not fall back to normal despite substantial ACE inhibition. For example, a study in 2000 by researchers in Spain showed that about 50% of congestive heart failure (CHF) patients had some form of ACE inhibitor escape. Escape was associated with poor prognosis. 2 When inhibitor escape occurs, clinicians may combine ACE inhibitors with angiotensin receptor blockers (ARBs), which prevent angiotensin II from binding its receptor, angiotensin II type 1 receptor (AGTR1). The rationale is that ACE inhibition should block some production of angiotensin II while ARBs will prevent the remaining angiotensin II from binding and activating AGTR1.Despite the biochemical rationale, the combination therapy has not always panned out in clinical trials when compared with either agent alone. Indeed, the side-effect profile of the combination has often outweighed any potential benefits. 3 Thus, many research groups have been searching for an ACEindependent angiotensin II production pathway to explain how ACE inhibitor escape occurs and to determine how to counteract the phenomenon.Ahsan Husain, professor of medicine at the Emory University School of Medicine, and colleagues think they might have an answer. The team previously focused on production of angiotensin II in mammalian hearts, in which they found that chymase localized to cardiac mast cells and catalyzed the formation of angiotensin II independent of ACE. [4][5][6][7] That finding suggested chymase might generate angiotensin II even in the presence of an ACE inhibitor and thus be at least partly responsible for ACE inhibitor escape. If so, inhibiting chymase could prevent escape and boost the efficacy of ACE inhibitors.To test that hypothesis, the group has now looked at an ACE inhibitor together with a chymase inhibitor in post-myocardial infarction (MI) hamsters. Compared with an ACE inhibitor, the combination improved left ventricle function, decreased adverse cardiac remodeling and improved survival.Additional studies in mice revealed a mechanism by which chronic ACE inhibition boosted chymase activity in the heart, contributing to ACE inhibitor escape. The missing link was bradykinin, a peptide that normally acts to dilate blood vessels. In addition to ACE inhibitors' intended effect of blocking ...

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“…Há evidências da existência de um SRA local em órgãos, tecidos e células (Kumar et al, 2007;Re, 2004). O SRA tecidual desempenha ações diferentes conforme os órgãos em que atua, tais como, proliferação e síntese proteica (Paul et al, 2006).…”

Section: Discussionunclassified

Sobrecarga e restrição de cloreto de sódio durante a gestação: repercussão sobre a estrutura cardíaca e renal no neonato

Nogueira¹

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AGRADECIMENTOSAgradeço primeiramente a Deus qυе iluminou о mеυ caminho durante este projeto e também agradeço a Nossa Senhora de Aparecida pela intercessão das graças recebidas.À minha família que nesta trajetória foi essencial pelo apoio incondicional e sacrifício imposto pela distância.Ao meu esposo Rodrigo, muito obrigada pelo carinho, pela paciência e por sua capacidade de me trazer a paz na correria diária. Você é uma pessoa incrível.À minha mãe Edite, um grande exemplo de mulher que superou as dificuldades da saúde para continuar me dando forças. Uma figura importantíssima na minha vida, uma mulher que sozinha buscou o melhor para suas filhas. Tenho muito orgulho de ser sua filha.À minha irmã querida, pelo apoio e carinho.À minha prima Carolina Rivas, pela força, pelo companheirismo de todos os dias durante esses três anos.Em especial, quero agradecer meu orientador Dr. Joel Claudio Heimann, um grande profissional ético e dedicado no seu trabalho árduo e contínuo. Tenho uma imensa gratidão por ter me recebido no seu grupo de pesquisa e ter acreditado em mim. Muito obrigada por estar sempre comigo nesta trajetória, seja no choro ou no riso, pelos ouvidos sempre disponíveis, pela cumplicidade e principalmente pela paciência. Por dizer-me não somente o que quero ouvir, mas As secretarias Solange e Denise.Aos técnicos e auxiliares, Janice, Claudia, Meire e Newton.À coordenação de pós-graduação.À FAPESP e a CAPES pelo apoio financeiro.

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The intracellular renin–angiotensin system: a new paradigm

Cited by 120 publications

References 83 publications

Intracellular angiotensin II activates rat myometrium

Intracellular angiotensin II activates rat myometrium

ACE in the hole

Sobrecarga e restrição de cloreto de sódio durante a gestação: repercussão sobre a estrutura cardíaca e renal no neonato

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