Autoantibody-mediated bladder dysfunction in type 1 diabetes.
Bladder dysfunction is a common complication of diabetic autonomic neuropathy; however, its cause remains uncertain. We have recently identified a novel IgG autoantibody (Ab) in patients with type 1 diabetes that acts as an agonist at the dihydropyridine (DHP) site of L-type voltage-gated calcium channels (VGCC), disrupting neuronal regulation of visceral smooth muscle. In the present study, passive transfer to mice of IgG from patients with type 1 diabetes was used to investigate the role of anti-VGCC Abs in mediating diabetic bladder dysfunction. Injection of mice with diabetic immunoglobulin (IgG) with anti-VGCC activity induced features of an overactive bladder, including phasic detrusor contractions and a loss of bladder wall compliance. The bladder overactivity is mimicked by the DHP agonist Bay K8644, reversed by the DHP antagonist nicardipine, but is insensitive to the motor nerve blocker tetrodotoxin, indicating that the anti-VGCC Ab acts at the level of the bladder detrusor itself. This study reports the first evidence of Ab-mediated bladder dysfunction in type 1 diabetes, which may be part of a wider spectrum of smooth muscle and cardiac abnormalities.
Wan
E-C
EC
Department of Immunology, Allergy & Arthritis, Flinders Medical Centre, Flinders University, Bedford Park, SA, Australia.
Gordon
T P
TP
Jackson
M W
MW
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D020746:Calcium Channels, L-Type / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009529:Nicardipine / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D001743:Urinary Bladder / Q000503:physiopathology; D001745:Urinary Bladder Diseases / Q000209:etiology*
D001323:Autoantibodies; D020746:Calcium Channels, L-Type; D013779:Tetrodotoxin; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D009529:Nicardipine