PKD1 haploinsufficiency is associated with altered vascular reactivity and abnormal calcium signaling in the mouse aorta.
Mutations in PKD1 are associated with autosomal dominant polycystic kidney disease (ADPKD), which leads to major cardiovascular complications. We used mice with a heterozygous deletion of Pkd1 (Pkd1+/-) and wild-type (Pkd1+/+) littermates to test whether Pkd1 haploinsufficiency is associated with a vascular phenotype in different age groups. Systolic blood pressure measured by the tail-cuff method was similar up to 20 weeks of age, but significantly higher in 30-week-old Pkd1+/- compared to Pkd1+/+. By contrast, similar telemetric recordings were obtained in unrestrained Pkd1+/- and Pkd1+/+ mice. The contractile responses evoked by KCl or phenylephrine were similar in young animals but increased in abdominal aortas of 30-week-old Pkd1+/- mice, and acetylcholine-evoked relaxation was depressed. Basal cytosolic calcium, KCl, and phenylephrine-evoked calcium signals were significantly lower in the Pkd1+/- aortas, whereas calcium release evoked by caffeine or thapsigargin was significantly larger. These changes were paralleled with a significant change in the mRNA expression of Pkd2, Trpc1, Orai1, and Serca2a in the aortas from Pkd1+/- vs. Pkd1+/+. These results are the first to indicate that haploinsufficiency in Pkd1 is associated with altered intracellular calcium homeostasis and increased vascular reactivity in the aorta with compensatory changes in transport proteins involved in the calcium signaling network.
Morel
Nicole
N
Laboratoire de Physiologie Cellulaire, Université Catholique de Louvain, Avenue Hippocrate 55, UCL 5540, Brussels, Belgium. nicole.morel@uclouvain.be
Vandenberg
Greet
G
Ahrabi
Ali K
AK
Caron
Nathalie
N
Desjardins
Fanny
F
Balligand
Jean-Luc
JL
Horie
Shigeo
S
Devuyst
Olivier
O
D000109:Acetylcholine / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000375:Aging / Q000502:physiology; D000818:Animals; D001011:Aorta / Q000033:anatomy & histology* / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D018678:Cholinergic Agents / Q000494:pharmacology; D004727:Endothelium / Q000502:physiology / Q000503:physiopathology; D018628:Gene Dosage; D006439:Hemodynamics; D006801:Humans; D007668:Kidney / Q000502:physiology; D008297:Male; D051379:Mice; D009129:Muscle Tonus / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics / Q000503:physiopathology; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D000109:Acetylcholine; D000316:Adrenergic alpha-Agonists; D002118:Calcium; D018678:Cholinergic Agents; D010656:Phenylephrine; D050396:TRPP Cation Channels