Myocardial enzymatic activity of renin and cathepsin D before and after bilateral nephrectomy

Katz, Stephen A.; Opsahl, John A.; Forbis, Lynn M.

doi:10.1007/s003950170019

Cited by 16 publications

(21 citation statements)

References 29 publications

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“…This concept is based on the inability to detect renin mRNA at cardiac tissue sites, 28,29 the disappearance of renin from the heart after bilateral nephrectomy, 2,3 and the lack of renin synthesis by cardiac fibroblasts and myocytes. 30,31 In fact, the majority of cardiac renin disappears within minutes when perfusing the heart with a renin-free buffer, 6 in full agreement with studies showing that cardiac renin is largely confined to the interstitial fluid compartment. 32,33 Obviously, some retention may occur at sites that do not readily exchange with the extracellular fluid compartment.…”

Section: Discussionsupporting

confidence: 71%

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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: Discussionsupporting

confidence: 71%

“…Thus, nonrenin enzymes like cathepsin D also contributed to the Ang I-generating activity in the homogenized rat heart. This has been noted before, 31 but does not necessarily imply that such nonrenin enzymes generate Ang I under in vivo circumstances.…”

Section: Discussionmentioning

confidence: 76%

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

et al. 2009

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“…Renin mRNA and protein has been demonstrated in cultured canine cardiac myocytes (26), and renin mRNA has been demonstrated in fibroblasts, as well as endothelial and coronary vascular smooth muscle cells (4,(27)(28)(29). Other studies conclude that there is no evidence for renin synthesis in normal adult rat myocytes (30). When we used anti-renin Abs, we observed immunostaining in mast cells in intact fixed heart sections.…”

Section: Discussionmentioning

confidence: 69%

Mast cells: A unique source of renin

Silver

Reid

Mackins

et al. 2004

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

175

159

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In addition to the traditional renin-angiotensin system, a great deal of evidence favors the existence of numerous independent tissue-specific renin-angiotensin systems. We report that mast cells are an additional source of renin and constitute a unique extrarenal renin-angiotensin system. We use renin-specific antibodies to demonstrate that cardiac mast cells contain renin. Extending this observation to the human mast cell line HMC-1, we show that these mast cells also express renin. The HMC-1 renin RT-PCR product is 100% homologous to Homo sapiens renin. HMC-1 cells also contain renin protein, as demonstrated both by immunoblot and immunocytochemical analyses. Renin released from HMC-1 cells is active; furthermore, HMC-1 cells are able to synthesize renin. It is known that, in the heart, mast cells are found in the interstitium in close proximity to nerves and myocytes, which both express angiotensin II receptors. Inasmuch as myocardial interstitium contains angiotensinogen and angiotensinconverting enzyme, and because we were able to detect renin only in mast cells, we postulate that the release of renin from cardiac mast cells is the pivotal event triggering local formation of angiotensin II. Because of the ubiquity of mast cells, our results represent a unique paradigm for understanding local renin-angiotensin systems, not just in the heart, but in all tissues. Our findings provide a rationale for targeting mast cells in conjunction with renin-angiotensin system inhibitors in the management of angiotensin II-related dysfunctions.T raditionally the renin-angiotensin system (RAS) has been viewed as a circulating axis, whereby renin is released into the circulation from the kidneys in response to decreased renal perfusion pressure, decreased delivery of NaCl at the macula densa, and͞or increased renal sympathetic nerve activity (1). The rate-limiting step in the formation of angiotensin II (ANG II) is the proteolytic action of renin, which cleaves angiotensinogen (Aogen) to the intermediate angiotensin I (ANG I). ANG I is then converted to ANG II by angiotensin-converting enzyme (ACE) at the endothelial surface (2, 3).In addition to this conventional pathway, many tissues, including heart and brain, are thought to be capable of local ANG II production via tissue-specific RAS (4, 5). Although Aogen, ANG I, and ACE, have been demonstrated in various organs, the presence of renin of extrarenal origin has been more difficult to prove and remains controversial. In this investigation, experiments were designed to determine whether renin could be detected in native tissue other than kidney. Because ANG II plays such a crucial role in cardiovascular disease, we focused our efforts on heart tissue, which we screened for renin by using an established polyclonal anti-renin Ab made to recombinant human renin (6). We found that cardiac mast cells were immunopositive for renin. In addition, we used a cultured mast cell line to extrapolate our observations from fixed heart slices to living cells.Our findings indicate that ma...

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“…25,43,47 Fourth, cultured neonatal and adult rat cardiac myocytes and fibroblasts do not release renin or its inactive precursor, prorenin, into the medium. 48,49 Taken together, therefore, it appears that the renin required for cardiac angiotensin generation is taken up from the circulation, ie, is kidney-derived. A similar concept applies to the vascular wall.…”

Section: Tissue Reninmentioning

confidence: 99%