title: Transgenic mice with ocular overexpression of an adrenomedullin receptor reflect human acute angle-closure glaucoma.
abstract: Glaucoma, frequently associated with high IOP (intra-ocular pressure), is a leading cause of blindness, characterized by a loss of retinal ganglion cells and the corresponding optic nerve fibres. In the present study, acutely and transiently elevated IOP, characteristic of acute angle-closure glaucoma in humans, was observed in CLR (calcitonin receptor-like receptor) transgenic mice between 1 and 3 months of age. Expression of CLR under the control of a smooth muscle alpha-actin promoter in these mice augmented signalling of the smooth-muscle-relaxing peptide adrenomedullin in the pupillary sphincter muscle and resulted in pupillary palsy. Elevated IOP was prevented in CLR transgenic mice when mated with hemizygote adrenomedullin-deficient mice with up to 50% lower plasma and organ adrenomedullin concentrations. This indicates that endogenous adrenomedullin of iris ciliary body origin causes pupillary palsy and angle closure in CLR transgenic mice overexpressing adrenomedullin receptors in the pupillary sphincter muscle. In human eyes, immunoreactive adrenomedullin has also been detected in the ciliary body. Furthermore, the CLR and RAMP2 (receptor-activity-modifying protein 2), constituting adrenomedullin receptor heterodimers, were identified in the human pupillary sphincter muscle. Thus, in humans, defective regulation of adrenomedullin action in the pupillary sphincter muscle, provoked in the present study in CLR transgenic mice, may cause acute and chronic atony and, thereby, contribute to the development of angle-closure glaucoma. The CLR transgenic mice used in the present study provide a model for acute angle-closure glaucoma.
authors.affiliation: Laboratory for Orthopedic Research, Orthopedic University Hospital Balgrist, University of Zurich, CH-8008 Zurich, Switzerland.
authors.forename: Lars M
authors.initials: LM
authors.lastname: Ittner
authors.forename: Kerstin
authors.initials: K
authors.lastname: Schwerdtfeger
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Kunz
authors.forename: Roman
authors.initials: R
authors.lastname: Muff
authors.forename: Knut
authors.initials: K
authors.lastname: Husmann
authors.forename: Christian
authors.initials: C
authors.lastname: Grimm
authors.forename: Farhad
authors.initials: F
authors.lastname: Hafezi
authors.forename: Karl S
authors.initials: KS
authors.lastname: Lang
authors.forename: Michael O
authors.initials: MO
authors.lastname: Kurrer
authors.forename: Jürgen
authors.initials: J
authors.lastname: Götz
authors.forename: Walter
authors.initials: W
authors.lastname: Born
authors.forename: Jan A
authors.initials: JA
authors.lastname: Fischer
mesh_terms: D000208:Acute Disease; D000818:Animals; D001483:Base Sequence; D058286:Calcitonin Receptor-Like Protein; D002924:Ciliary Body / Q000378:metabolism; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000235:genetics; D015812:Glaucoma, Angle-Closure / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D007429:Intraocular Pressure; D007498:Iris / Q000503:physiopathology; D007499:Iris Diseases / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010088:Oxidoreductases / Q000235:genetics; D058265:Receptors, Adrenomedullin; D018003:Receptors, Calcitonin / Q000378:metabolism / Q000502:physiology; D018000:Receptors, Peptide / Q000378:metabolism*
chemical_list: C545578:CALCRL protein, human; D058286:Calcitonin Receptor-Like Protein; C545579:Calcrl protein, mouse; D005136:Eye Proteins; C445671:Gpnmb protein, mouse; D008562:Membrane Glycoproteins; D058265:Receptors, Adrenomedullin; D018003:Receptors, Calcitonin; D018000:Receptors, Peptide; D010088:Oxidoreductases; C079621:Tyrp1 protein, mouse