title: Dense-core vesicle proteins IA-2 and IA-2{beta} affect renin synthesis and secretion through the {beta}-adrenergic pathway.
abstract: IA-2 and IA-2beta, major autoantigens in type 1 diabetes, are transmembrane proteins in dense-core vesicles, and their expression influences the secretion of hormones and neurotransmitters. The present experiments were performed to examine whether IA-2 and IA-2beta modulate the release of renin from dense-core vesicles of juxtaglomerular granular cells in the kidney. Plasma renin concentration (PRC; ng angiotensin I.ml(-1).h(-1)) was significantly reduced in mice with null mutations in IA-2, IA-2beta, or both IA-2 and IA-2beta compared with wild-type mice (876 +/- 113, 962 +/- 130, and 596 +/- 82 vs. 1,367 +/- 93; P < 0.01, P < 0.02, and P < 0.001). Renin mRNA levels were reduced to 26.4 +/- 5.1, 39 +/- 5.4, and 35.3 +/- 5.5% of wild-type in IA-2-/-, IA-2beta-/-, and IA-2/IA-2beta-/- mice. Plasma aldosterone levels were not significantly different among genotypes. The regulation of PRC by furosemide and salt intake, and of aldosterone by salt intake, was maintained in all genotypes. IA-2 and IA-2beta expression did not colocalize with renin but showed overlapping immunoreactivity with tyrosine hydroxylase. While propranolol reduced PRC in wild-type mice, it had no effect on PRC in IA-2/ IA-2beta-/- mice. Renal tyrosine hydroxylase mRNA and immunoreactivity were reduced in IA-2/IA-2beta-/- mice as was the urinary excretion of catecholamines. We conclude that IA-2 and IA-2beta are required to maintain normal levels of renin expression and renin release, most likely by permitting normal rates of catecholamine release from sympathetic nerve terminals.
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg. 10, Rm. 4D51, 10 Center Dr.-MSC 1370, Bethesda, MD 20892, USA.
authors.forename: Soo Mi
authors.initials: SM
authors.lastname: Kim
authors.forename: Franziska
authors.initials: F
authors.lastname: Theilig
authors.forename: Yan
authors.initials: Y
authors.lastname: Qin
authors.forename: Tao
authors.initials: T
authors.lastname: Cai
authors.forename: Diane
authors.initials: D
authors.lastname: Mizel
authors.forename: Robert
authors.initials: R
authors.lastname: Faulhaber-Walter
authors.forename: Hiroki
authors.initials: H
authors.lastname: Hirai
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bachmann
authors.forename: Josephine P
authors.initials: JP
authors.lastname: Briggs
authors.forename: Abner L
authors.initials: AL
authors.lastname: Notkins
authors.forename: Jurgen
authors.initials: J
authors.lastname: Schnermann
mesh_terms: D000320:Adrenergic Fibers / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure; D005260:Female; D005919:Glomerular Filtration Rate; D007606:Juxtaglomerular Apparatus / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000502:physiology*; D012083:Renin / Q000096:biosynthesis* / Q000097:blood / Q000378:metabolism; D012084:Renin-Angiotensin System; D022142:Secretory Vesicles / Q000378:metabolism*
chemical_list: C516863:Ptprn protein, mouse; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D012083:Renin