title: Pkd2 mesenteric vessels exhibit a primary defect in endothelium-dependent vasodilatation restored by rosiglitazone.
abstract: Patients with autosomal dominant polycystic kidney disease have a high prevalence of hypertension and structural vascular abnormalities, such as intracranial aneurysms. Hypertension can develop in childhood and often precedes a significant reduction in the glomerular filtration rate. The major aim of this study was to investigate whether a primary endothelial defect or a vascular smooth muscle (VSM) defect was present in murine polycystic kidney disease (Pkd)2 heterozygous mesenteric vessels before the development of renal failure or hypertension. Using pressure myography, we observed a marked defect in ACh-stimulated endothelium-dependent vasodilatation in Pkd2 arterioles. In contrast, Pkd2 vessels responded normally to sodium nitroprusside, phenylephrine, KCl, and pressure, indicating unaltered VSM-dependent responses. Pretreatment with the peroxisome proliferator-activated receptor-γ agonist rosiglitazone significantly restored ACh-dependent vasodilation in Pkd2 mice. Isolated heterozygous Pkd2 endothelial cells displayed normal ACh-stimulated Ca(2+) and nitric oxide production. However, isolated Pkd2 heterozygous VSM cells displayed basal increases in superoxide and sodium nitroprusside-stimulated peroxynitrite formation, which were both suppressed by rosiglitazone. Furthermore, we observed a defective response of Pkd2 mesenteric venules to ACh in vivo, which was more marked after ischemia-reperfusion injury. In conclusion, the results of our study suggest that the defect in vasodilatation in Pkd2 heterozygous vessels is primarily due to a reduction in nitric bioavailability secondary to increased vascular oxidative stress. The ability of rosiglitazone to correct this phenotype suggests that this defect is potentially reversible in patients with autosomal dominant polycystic kidney disease.
authors.affiliation: Microcirculation Research Group, Department of Cardiovascular Science, University of Sheffield Medical School, Beech Hill Road, Sheffield, UK.
authors.forename: Zoë L S
authors.initials: ZL
authors.lastname: Brookes
authors.forename: Lewis
authors.initials: L
authors.lastname: Ruff
authors.forename: Viralkumar S
authors.initials: VS
authors.lastname: Upadhyay
authors.forename: Linghong
authors.initials: L
authors.lastname: Huang
authors.forename: Sony
authors.initials: S
authors.lastname: Prasad
authors.forename: Tirupa
authors.initials: T
authors.lastname: Solanky
authors.forename: Surya M
authors.initials: SM
authors.lastname: Nauli
authors.forename: Albert C M
authors.initials: AC
authors.lastname: Ong
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D005838:Genotype; D006579:Heterozygote; D006973:Hypertension / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008643:Mesentery / Q000098:blood supply*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009213:Myography; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism; D010641:Phenotype; D016891:Polycystic Kidney, Autosomal Dominant / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051437:Renal Insufficiency / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000077154:Rosiglitazone; D013481:Superoxides / Q000378:metabolism; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology*; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology; D014699:Venules / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology
chemical_list: D000975:Antioxidants; D002118:Calcium; D009569:Nitric Oxide; D047495:PPAR gamma; D030421:Peroxynitrous Acid; D000077154:Rosiglitazone; D013481:Superoxides; D050396:TRPP Cation Channels; D045162:Thiazolidinediones; D014665:Vasodilator Agents