Transendothelial transport of renin–angiotensin system components

Eijnden, Mark M. E. D. van den; Bruin, René J.A. de; Wit, E. de; Sluiter, Wim J.; Deinum, Jaap; Reudelhuber, Timothy L.; Danser, A.H. Jan

doi:10.1097/00004872-200210000-00023

Cited by 17 publications

(12 citation statements)

References 34 publications

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“…For instance, M6PR-internalized (pro)renin is cleared intracellularly (with a half-life of several hours 8,34 ) without being released to the extracellular fluid. 5,35 In addition, renin stored in mast cell granules would only be released after exposure to a mast cell degranulator.…”

Section: Discussionmentioning

confidence: 99%

“…1 Yet, the renin required for this Ang generation is largely, if not completely, derived from the kidney, because after a bilateral nephrectomy, both cardiac renin and Ang II decrease to undetectable levels. [2][3][4] Circulating, kidney-derived renin diffuses into cardiac interstitial fluid 5 and/or binds to "renin receptors." In support of this concept, the washout of renin from isolated perfused rat Langendorff hearts loaded with porcine renin followed a biphasic pattern: an initial, rapid (half-life: Ͻ0.5 minutes) phase representing a disappearance from the extracellular fluid compartment and a secondary, slower phase (half-life: Ϸ3 to 4 minutes), representing a disappearance from tissue sites, possibly cell-surface renin receptors.…”

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confidence: 99%

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Cardiac Renin Levels Are Not Influenced by the Amount of Resident Mast Cells

et al. 2009

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Abstract-To investigate whether mast cells release renin in the heart, we studied renin and prorenin synthesis by such cells, using the human mast cell lines human mastocytoma 1 and LAD2, as well as fresh mast cells from mastocytosis patients. We also quantified the contribution of mast cells to cardiac renin levels in control and infarcted rat hearts. Human mastocytoma 1 cells contained and released angiotensin I-generating activity, and the inhibition of this activity by the renin inhibitor aliskiren was comparable to that of recombinant human renin. Prorenin activation with trypsin increased angiotensin I-generating activity in the medium only, suggesting release but not storage of prorenin. The adenylyl cyclase activator forskolin, the cAMP analogue 8-db-cAMP, and the degranulator compound 48/80 increased renin release without affecting prorenin. Angiotensin II blocked the forskolin-induced renin release. Angiotensin I-generating activity was undetectable in LAD2 cells and fresh mast cells. Nonperfused rat hearts contained angiotensin I-generating activity, and aliskiren blocked Ϸ70% of this activity. A 30-minute buffer perfusion washed away Ͼ70% of the aliskiren-inhibitable angiotensin I-generating activity. Prolonged buffer perfusion or compound 48/80 did not decrease cardiac angiotensin I-generating activity further or induce angiotensin I-generating activity release in the perfusion buffer. Results in infarcted hearts were identical, despite the increased mast cell number in such hearts. In conclusion, human mastocytoma 1 cells release renin and prorenin, and the regulation of this release resembles that of renal renin. However, this is not a uniform property of all mast cells. Mast cells appear an unlikely source of renin in the heart, both under normal and pathophysiological conditions. (Hypertension. 2009;54:315-321.)

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Cardiac Renin Levels Are Not Influenced by the Amount of Resident Mast Cells

et al. 2009

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“…[34][35][36] Renin sequestration may occur by simple diffusion into the interstitium and/or binding to a receptor. [37][38][39] Alternatively, prorenin, the inactive precursor of renin, might contribute to tissue Ang production, particularly because its plasma levels are much higher than those of renin. 27 If true, a local prorenin-reninconverting mechanism should exist, to allow prorenin to display activity at tissue sites.…”

Section: Angiotensin-independent Effects Of (Pro)renin: Activation Ofmentioning

confidence: 99%

The increase in renin during renin inhibition: does it result in harmful effects by the (pro)renin receptor?

Danser

2009

Hypertens Res

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Renin inhibitors, similar to all renin-angiotensin system (RAS) blockers, increase the plasma concentration of renin because they attenuate the negative feedback effect of angiotensin (Ang) II on renin release. The increase in renin has been suggested to be higher than that during other types of RAS blockade. This could potentially limit the effectiveness of renin inhibition, either because Ang II generation might occur again ('Ang II escape'), possibly even at the levels above baseline, as has been described before for angiotensin-converting enzyme inhibitors, or because high levels of renin will stimulate the recently discovered (pro)renin receptor, and thus induce effects in an Ang-independent manner. This review shows first that the cause(s) of the renin increase during treatment with the renin inhibitor aliskiren is the consequence of a combination of factors, including an assay artifact, allowing the detection of prorenin as renin, and a change in renin half-life. When correcting for these phenomena the increase is unlikely to be as excessive as originally thought. The review then critically describes the consequence(s) of such a increase, concluding (i) that an Ang II escape is highly unlikely, given the [aliskiren]/[renin] stoichiometry, and (ii) that renin and prorenin downregulate their receptor (similar to many agonists). On the basis of the latter, one could even speculate that this will be more substantial when the renin and prorenin levels are higher. Thus, from this point of view the larger increase in renin during renin inhibition will cause a stronger reduction in (pro)renin receptor expression, and a greater suppression of (pro)renin receptor-mediated effects than other renin-Ang blockers.

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“…The cardiac renin levels per se (expressed per gram wet weight) are too high to be explained based on the amount of (renin-containing and prorenincontaining) blood plasma (Ϸ5%) in the heart. 6,43 Thus, circulating renin and prorenin either diffuse into the interstitial space 59 and/or bind to (pro)renin receptors. Diffusion is supported by studies in a modified version of the isolated perfused rat Langendorff heart, allowing separate collection of coronary effluent and interstitial transudate.…”

Section: Sequestration Of Circulating (Pro)renin: Diffusion or A Recementioning

confidence: 99%