Submitted on September 15, 2008
Revised on November 4, 2008
Accepted on November 13, 2008
Dense Core Vesicle Proteins IA-2 and IA-2
affect Renin Synthesis and Secretion through the -Adrenergic Pathway
Soo Mi Kim1, Franziska Theilig2, Yan Qin1, Tao Cai1, Diane Mizel, Robert Faulhaber-Walter1, Hiroki Hirai1, Sebastian Bachmann3, Josephine P Briggs1, Abner L Notkins1, and Jurgen B Schnermann4*
1 NIH
2 Charite - Universitatsmedizin Berlin
3 Charit Berlin
4 NIDDK, NIH
* To whom correspondence should be addressed. E-mail: jurgens{at}intra.niddk.nih.gov.
IA-2 and IA-2
, 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 modulate the release of renin from dense core vesicles of juxtaglomerular granular cells in the kidney. Plasma renin concentration (PRC; ng angiotensin I/ml hr) was significantly reduced in mice with null mutations in IA-2, IA-2, or both IA-2 and IA-2 compared to wild type mice (876 ± 113, 962 ± 130, and 596 ± 82 vs. 1367 ± 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-2-/-, and IA2/IA-2-/- mice. Plasma aldosterone levels were not significantly different between 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 expression did not co-localize 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-/- mice. Renal tyrosine hydroxylase mRNA and immunoreactivity was reduced in IA-2/ IA-2-/- mice. We conclude that IA-2 and IA-2 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.
