Mast cell renin and a local renin–angiotensin system in the airway: Role in bronchoconstriction

Abstract

We previously reported that mast cells express renin, the ratelimiting enzyme in the renin-angiotensin cascade. We have now assessed whether mast cell renin release triggers angiotensin formation in the airway. In isolated rat bronchial rings, mast cell degranulation released enzyme with angiotensin I-forming activity blocked by the selective renin inhibitor BILA2157. Local generation of angiotensin (ANG II) from mast cell renin elicited bronchial smooth muscle contraction mediated by ANG II type 1 receptors (AT 1R). In a guinea pig model of immediate type hypersensitivity, anaphylactic mast cell degranulation in bronchial rings resulted in ANG II-mediated constriction. As in rat bronchial rings, bronchoconstriction (BC) was inhibited by a renin inhibitor, an AT 1R blocker, and a mast cell stabilizer. Anaphylactic release of renin, histamine, and ␤-hexosaminidase from mast cells was confirmed in the effluent from isolated, perfused guinea pig lung. To relate the significance of this finding to humans, mast cells were isolated from macroscopically normal human lung waste tissue specimens. Sequence analysis of human lung mast cell RNA showed 100% homology between human lung mast cell renin and kidney renin between exons 1 and 10. Furthermore, the renin protein expressed in lung mast cells was enzymatically active. Our results demonstrate the existence of an airway renin-angiotensin system triggered by release of mast-cell renin. The data show that locally produced ANG II is a critical factor governing BC, opening the possibility for novel therapeutic targets in the management of airway disease.angiotensin II ͉ angiotensin II type 1 receptors ͉ asthma ͉ hypersensitivity ͉ lung T he renin-angiotensin system (RAS) has been traditionally 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, and/or increased renal sympathetic nerve activity (1). The proteolytic cleavage of angiotensinogen (aogen) by renin constitutes the rate-limiting step of the RAS cascade.In addition to this classical view, it is believed that many tissues, including the lung, may possess the capacity to generate angiotensin (ANG II) locally (2, 3). This is supported by experiments demonstrating that ANG II persists in lung of nephrectomized rats (4) and findings showing that ANG II can be elevated in the lungs in the absence of an elevated systemic RAS (5). Components of RAS have been identified in lung tissue, including aogen mRNA (6, 7), and angiotensin-converting enzyme (ACE), the pulmonary endothelium being the primary source for ACE in the body (8). ANG II receptors are also expressed in lung tissue, with the ANG II type 1 receptor (AT 1 R) subtype found on bronchial smooth muscle cells (9) and ANG II type 2 receptor (AT 2 R) observed on the bronchial epithelial cell brush border (10). An intrapulmonary source of renin protein has not yet been identified.We previously reported that mast cells synthesize, st...

Mast Cells: A Pivotal Role in Pulmonary Fibrosis

“…1A, bottom). Since mast cells are a major source of histamine and renin (Veerappan et al, 2008), their levels were measured in lung homogenates from saline-and bleomycintreated mice. Histamine levels were greatest in the homogenates from the CC-Bleo compared with the CC-Sal mice (Fig.…”

“…For the mast cell reconstitution experiments, mast cells were immuno-magnetically isolated from the lungs of CC littermates. Aliquots of isolated mast cells were re-suspended in phosphate-buffered saline (PBS) for intra-tracheal instillation in MCD mice (*300,000 mast cells/mouse) as previously described (Worgall et al, 1999;Veerappan et al, 2008). Bleomycin or saline instillation followed 2 weeks later.…”

“…Immunocytochemistry was performed as previously described (Silver et al, 2004;Veerappan et al, 2008Veerappan et al, , 2011. Primary antibodies used were goat anti-AT 1 R (1:50) and rabbit anti-H 1 R antibodies (1:50) (SCBT).…”

“…TGF-b also stimulates the expression of ANG II AT 1 R in lung fibroblasts . We previously reported that lung mast cells synthesize and release renin, which triggers local ANG II formation (Silver et al, 2004;Veerappan et al, 2008). Histamine, another mast cell mediator, may also contribute to fibrosis by stimulating fibroblast proliferation ( Jordana et al, 1988).…”

“…Specifically, mast cell mediators, such as histamine and renin, the latter leading to locally formed ANG II (Silver et al, 2004;Veerappan et al, 2008), released in close proximity to fibroblasts, lead to fibrogenesis. Our hypothesis was tested utilizing mast-cell-deficient WBB6F 1 -W/W v (MCD) mice and their congenic controls WBB6F 1 -+ / + (CC).…”