Testicular hormonal regulation of the renin-angiotensin system in the rat epididymis

Leung, Po Sing; Wong, Tung Po; Lam, Sarah; Chan, Hsiao Chang; Wong, Pui Ting

doi:10.1016/s0024-3205(00)00439-2

Cited by 38 publications

(23 citation statements)

References 23 publications

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“…The identification of tissue-specific RAS, where locally generated ANG II acts on resident receptors, has gained considerable attention, especially in heart (4), brain (22), eye (23,24), and testis (25). Here, we report that mast cells constitute an additional source of renin that contributes to tissue-specific RAS.…”

Section: Discussionmentioning

confidence: 90%

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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Section: Discussionmentioning

confidence: 90%

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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“…However, gender differences in risk factor susceptibility could be also explained by upregulation of AT 1 receptor expression and activation of the renin angiotensin system via androgens. 56,57 These findings suggest that either ACE inhibitors or AT 1 receptor antagonists may be beneficial in the postmenopausal state to antagonize the effect of increased AT 1 receptor expression.…”

Section: Regulation Of At 1 Receptor Expressionmentioning

confidence: 94%

The AT ₁ -Type Angiotensin Receptor in Oxidative Stress and Atherogenesis

2002

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D espite intense investigation in the last decade, many questions concerning the etiology of atherosclerosis remain unanswered. Hypercholesterolemia and hypertension are clearly risk factors for the development of vascular lesions, although the precise molecular steps between elevated lipid or blood pressure levels and the development of atherosclerotic lesions are not completely defined. 1,2 Hypertension is frequently associated with additional risk factors such as hypercholesterolemia, estrogen deficiency, or hyperinsulinemia. This clustering of risk factors greatly enhances the probability to develop atherosclerosis. 3 Nevertheless, the cellular events responsible for the mutual appearance of several risk factors are poorly understood. A series of recent studies have addressed the hypothesis that enhanced AT 1 receptor activation could explain the association of various hormonal and metabolic disorders with hypertension, and ultimately, with accelerated progression of vascular lesions. Regulation of AT 1 Receptor Expression and FunctionAs early as 1980, Alexander and colleagues discovered that the vasoconstriction caused by angiotensin II in resistance vessels was variable. 4 Further investigations revealed that AT 1 receptor activation is subject to a negative feedback, in that increased levels of angiotensin II diminish and decreased angiotensin II concentrations enhance AT 1 receptor activation. [5][6][7][8] More recently, it has been shown that multiple agonists other than angiotensin II modulate AT 1 receptor expression. This phenomenon, referred to as heterologous AT 1 receptor regulation, is induced by various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), or fibroblast growth factor (FGF), all which downregulate AT 1 receptor expression. 9 Numerous other factors, including glucocorticoids, aldosterone, forskolin, TNF␣, cytokines, nitric oxide, insulin, LDL, estrogen, progesterone, sodium, free radicals, IGF-1, and isoprenaline are known to influence AT 1 receptor expression (Table). 10 -38 Hypercholesterolemia-Associated AT 1 Receptor OverexpressionHypercholesterolemia and in particular elevated LDL plasma concentrations play a fundamental role in the pathogenesis of atherosclerosis, as shown by numerous epidemiological and interventional studies. 1,2 Moreover, hypercholesterolemia is frequently associated with hypertension, another potent cardiovascular risk factor. 3 Despite this large body of epidemiological evidence, the molecular events leading from hypercholesterolemia to hypertension and atherosclerosis are only partially understood. Recent studies have provided insight into these interactions. For example, it has been shown that exposure of vascular smooth muscle cells to LDL markedly augments AT 1 receptor mRNA and protein expression. 39 Consistent with these findings, the functional response of these cells on angiotensin II stimulation (eg, calcium release, cell proliferation) is also enhanced. The underlying mechanism for this upregulation of...

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“…In a study by Nickenig et al [43], in ovariectomized rats and cultured vascular smooth muscle cells, estrogen down-regulated AT 1 receptor expression. Conversely, Leung et al [44] studied male rats and found that castration abolishes, and testosterone replacement enhances, AT 1 receptor expression in the epididymus. These observations demonstrate that gender appears to have an important impact on the RAS via AT 1 receptor expression.…”

Section: Gender Differences In Renin-angiotensin System Functionmentioning

confidence: 99%

Effects of gender on the renin-Angiotensin system, blood pressure, and renal function

Kang

Miller

2002

Current Science Inc

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Recent studies have identified key gender differences in cardiovascular function, renal hemodynamics, and the renin-angiotensin system. Extensive epidemiologic evidence has shown a clear gender difference in cardiovascular and renal disease progression, whereby female sex appears to be protective. The mechanisms underlying this phenomenon are unknown, but likely reflect the aforementioned sex differences in common pathophysiologic pathways. This review focuses on studies examining sex differences in these underlying pathways, which together may provide a plausible mechanism for the gender disparity in clinical outcomes.

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Testicular hormonal regulation of the renin-angiotensin system in the rat epididymis

Cited by 38 publications

References 23 publications

Mast cells: A unique source of renin

Mast cells: A unique source of renin

The AT ₁ -Type Angiotensin Receptor in Oxidative Stress and Atherogenesis

Effects of gender on the renin-Angiotensin system, blood pressure, and renal function

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Testicular hormonal regulation of the renin-angiotensin system in the rat epididymis

Cited by 38 publications

References 23 publications

Mast cells: A unique source of renin

Mast cells: A unique source of renin

The AT 1 -Type Angiotensin Receptor in Oxidative Stress and Atherogenesis

Effects of gender on the renin-Angiotensin system, blood pressure, and renal function

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Resources

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The AT ₁ -Type Angiotensin Receptor in Oxidative Stress and Atherogenesis