title: Upregulation of a local renin-angiotensin system in the rat carotid body during chronic intermittent hypoxia.
abstract: The carotid body (CB) plays an important role in the alteration of cardiorespiratory activity in chronic intermittent hypoxia (IH) associated with sleep-disordered breathing, which may be mediated by local expression of the renin-angiotensin system (RAS). We hypothesized a pathogenic role for IH-induced RAS expression in the CB. The CB expression of RAS components was examined in rats exposed to IH resembling a severe sleep-apnoeic condition for 7 days. In situ hybridization showed an elevated expression of angiotensinogen in the CB glomus cells in the hypoxic group when compared with the normoxic control group. Immunohistochemical studies and Western blot analysis revealed increases in the protein level of both angiotensinogen and angiotensin II type 1 (AT1) receptors in the hypoxic group, which were localized to the glomic clusters containing tyrosine hydroxylase. RT-PCR studies confirmed that levels of the mRNA expression of angiotensinogen, angiotensin-converting enzyme, AT1a and AT2 receptors were significantly increased in the CBs of the hypoxic rats. Functionally, the [Ca(2+)]i response to exogenous angiotensin II was enhanced in fura-2-loaded glomus cells dissociated from hypoxic rats when compared with those of the normoxic control animals. Pretreatment with losartan, but not PD123319, abolished the angiotensin II-induced [Ca(2+)]i response, suggesting an involvement of AT1 receptors. Moreover, daily treatment of the IH group of rats with losartan attenuated the levels of oxidative stress, gp91(phox) expression and macrophage infiltration in the CB. Collectively, the upregulated local RAS expression could play a pathogenic role in the augmented CB activity and local inflammation via AT1 receptor activation during IH conditions in patients with sleep-disordered breathing.
authors.affiliation: M. L. Fung: Department of Physiology, University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong. fungml@hku.hk.
authors.forename: Siu-Yin
authors.initials: SY
authors.lastname: Lam
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.forename: Kwong-Man
authors.initials: KM
authors.lastname: Ng
authors.forename: Emily C
authors.initials: EC
authors.lastname: Liong
authors.forename: George L
authors.initials: GL
authors.lastname: Tipoe
authors.forename: Po Sing
authors.initials: PS
authors.lastname: Leung
authors.forename: Man-Lung
authors.initials: ML
authors.lastname: Fung
mesh_terms: D000804:Angiotensin II / Q000235:genetics / Q000378:metabolism; D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002344:Carotid Body / Q000378:metabolism*; D016257:Fura-2 / Q000378:metabolism; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000235:genetics*; D012891:Sleep Apnea Syndromes / Q000235:genetics / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D008562:Membrane Glycoproteins; D044140:Receptor, Angiotensin, Type 1; D000808:Angiotensinogen; D000804:Angiotensin II; D014446:Tyrosine 3-Monooxygenase; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D007703:Peptidyl-Dipeptidase A; D002118:Calcium; D016257:Fura-2