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

IA-2 and IA-2[beta], 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-2[beta] modulate the release of renin from dense-core vesicles of juxtaglomerular granular cells in the kidney. Plasma renin concentration (PRC; ng angiotensin I * [ml.sup.-1] * [h.sup.-1]) was significantly reduced in mice with null mutations in IA-2, IA-2[beta], or both IA-2 and IA-2[beta] compared with wild-type mice (876 [+ or -] 113, 962 [+ or -] 130, and 596 [+ or -] 82 vs. 1,367 + 93; P < 0.01, P < 0.02, and P < 0.001). Renin mRNA levels were reduced to 26.4 [+ or -] 5.1, 39 [+ or -] 5.4, and 35.3 [+ or -] 5.5% of wild-type in IA-2-/-, IA-2[beta]-/-, and IA-2/IA-2[beta]-/- 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-2[beta] 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-2[beta]-/- mice. Renal tyrosine hydroxylase mRNA and immunoreactivity were reduced in IA-2/IA-2[beta]-/- mice as was the urinary excretion of catecholamines. We conclude that IA-2 and IA-2[beta] 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