Dense-core vesicle proteins IA-2 and IA-2{beta} affect renin synthesis and secretion through the {beta}-adrenergic pathway.
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.
Kim
Soo Mi
SM
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.
Theilig
Franziska
F
Qin
Yan
Y
Cai
Tao
T
Mizel
Diane
D
Faulhaber-Walter
Robert
R
Hirai
Hiroki
H
Bachmann
Sebastian
S
Briggs
Josephine P
JP
Notkins
Abner L
AL
Schnermann
Jurgen
J
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*
C516863:Ptprn protein, mouse; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D012083:Renin