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This Article Full Text Full Text (PDF) All Versions of this Article: 296/2/F382    most recent 90543.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Kim, S. M. Articles by Schnermann, J. Search for Related Content PubMed PubMed Citation Articles by Kim, S. M. Articles by Schnermann, J.

Dense-core vesicle proteins IA-2 and IA-2β affect renin synthesis and secretion through the β-adrenergic pathway

¹National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda; ²Institute of Anatomy, Charite, Berlin, Germany; and ³National Institute of Dental and Craniofacial Research, National Institute of Child Health and Human Development, and ⁴National Center of Complementary and Alternative Medicine, National Institutes of Health, Bethesda, Maryland

Submitted 15 September 2008 ; accepted in final form 13 November 2008

IA-2 and IA-2β, 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-2β 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-2β, or both IA-2 and IA-2β 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-2β–/–, and IA-2/IA-2β–/– 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-2β 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-2β–/– mice. Renal tyrosine hydroxylase mRNA and immunoreactivity were reduced in IA-2/IA-2β–/– mice as was the urinary excretion of catecholamines. We conclude that IA-2 and IA-2β 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.

knockout mice; renin mRNA; propranolol; blood pressure; heart rate; salt intake