title: Endothelial dysfunction occurs prior to clinical evidence of polycystic kidney disease.
abstract: OBJECTIVE
  Polycystic kidney disease (PKD), a monogenic disease with an autosomal dominant or an autosomal recessive form of inheritance (ARPKD), is the most common genetic cause of renal dysfunction and end-stage renal failure. In addition to the development of cysts, the autosomal form of PKD is associated with vascular endothelial dysfunction, a marker of vascular disease. Whether vascular endothelial dysfunction is also present in ARPKD, and its relationship with renal dysfunction remain to be determined.
  
  
  METHODS
  ARPKD rats (PCK model) and controls were studied at 6 and 10 weeks of age, and mean arterial pressure and renal function were measured. Aortic endothelial function was assessed using organ chamber techniques. Aortic endothelial cells (ECs) were isolated, characterized and their function studied.
  
  
  RESULTS
  Compared to controls, ARPKD animals had a decrease in the vasorelaxation to endothelium-dependent vasodilators, even prior to changes in mean arterial pressure or renal function. The abnormal vasoreactivity was corrected with L-arginine (a precursor of nitric oxide, NO), while the expression of endothelial NO synthase (eNOS) was unchanged. Furthermore, isolated ECs from 6-week-old ARPKD animals showed increased oxidative stress, with preserved eNOS expression and abnormal patterns of migration and angiogenic capacity (measured by the scratch and tube formation assays, respectively).
  
  
  CONCLUSIONS
  ARPKD leads to impairments in aortic vascular function and ECs at an early stage, which can have significant functional consequences, potentially representing a novel therapeutic target in this disease.
authors.affiliation: Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, Minn., USA.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Peterson
authors.forename: Federico
authors.initials: F
authors.lastname: Franchi
authors.forename: Darrel L
authors.initials: DL
authors.lastname: Loeffler
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Psaltis
authors.forename: Peter C
authors.initials: PC
authors.lastname: Harris
authors.forename: Lilach O
authors.initials: LO
authors.lastname: Lerman
authors.forename: Amir
authors.initials: A
authors.lastname: Lerman
authors.forename: Martin
authors.initials: M
authors.lastname: Rodriguez-Porcel
mesh_terms: D000109:Acetylcholine / Q000737:chemistry; D000818:Animals; D001011:Aorta / Q000473:pathology; D049109:Cell Proliferation; D002470:Cell Survival; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology; D004730:Endothelium, Vascular / Q000473:pathology*; D005260:Female; D006439:Hemodynamics; D007668:Kidney / Q000473:pathology; D009569:Nitric Oxide / Q000737:chemistry; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress; D007690:Polycystic Kidney Diseases / Q000150:complications / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014652:Vascular Diseases / Q000150:complications / Q000473:pathology*
chemical_list: D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D000109:Acetylcholine