Mast cell renin and a local renin-angiotensin system in the airway: role in bronchoconstriction.
We previously reported that mast cells express renin, the rate-limiting 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(1)R). 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(1)R blocker, and a mast cell stabilizer. Anaphylactic release of renin, histamine, and beta-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.
Veerappan
Arul
A
Department of Physiology and Biophysics, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
Reid
Alicia C
AC
Estephan
Racha
R
O'Connor
Nathan
N
Thadani-Mulero
Maria
M
Salazar-Rodriguez
Mariselis
M
Levi
Roberto
R
Silver
Randi B
RB
D000804:Angiotensin II / Q000096:biosynthesis / Q000502:physiology; D000818:Animals; D001980:Bronchi / Q000201:enzymology* / Q000378:metabolism / Q000502:physiology; D016084:Bronchoconstriction / Q000502:physiology*; D015550:Cell Degranulation / Q000502:physiology; D006168:Guinea Pigs; D006801:Humans; D008168:Lung / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D008297:Male; D008407:Mast Cells / Q000201:enzymology* / Q000378:metabolism / Q000502:physiology; D009119:Muscle Contraction / Q000502:physiology; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D012083:Renin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D012084:Renin-Angiotensin System / Q000502:physiology*
D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D012083:Renin