title: Chronic renal failure alters endothelial function in cerebral circulation in mice.
abstract: We examined structure, composition, and endothelial function in cerebral arterioles after 4 wk of chronic renal failure (CRF) in a well-defined murine model (C57BL/6J and apolipoprotein E knockout female mice). We also determined quantitative expression of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (on serine 1177 and threonine 495), and caveolin-1; quantitative expression of markers of vascular inflammation or oxidative stress [Rock-1, Rock-2, VCAM-1, and peroxisome proliferator-activated receptor-γ (PPARγ)]; and the plasma concentration of L-arginine and asymmetric dimethylarginine (ADMA). Our hypothesis was that endothelial function would be impaired in cerebral arterioles during CRF following either a decrease in NO production (through alteration of eNOS expression or regulation) or an increase in NO degradation (due to oxidative stress or vascular inflammation). Endothelium-dependent relaxation was impaired during CRF, but endothelium-independent relaxation was not. CRF had no effect on cerebral arteriolar structure and composition. Quantitative expressions of eNOS, eNOS phosphorylated on serine 1177, caveolin-1, Rock-1, Rock-2, and VCAM-1 were similar in CRF and non-CRF mice. In contrast, quantitative expression of PPARγ (which exercises a protective role on blood vessels) was significantly lower in CRF mice, whereas quantitative expression of eNOS phosphorylated on the threonine 495 (the inactive form of eNOS) was significantly higher. Lastly, the plasma concentration of ADMA (a uremic toxin and an endogenous inhibitor of eNOS) was elevated and plasma concentration of L-arginine was low in CRF. In conclusion, endothelial function is impaired in a mouse model of early stage CRF. These alterations may be related (at least in part) to a decrease in NO production.
authors.affiliation: Institut National de Santé et de Recherche Médicale, ERI12, Amiens, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Bugnicourt
authors.forename: Charlène
authors.initials: C
authors.lastname: Da Silveira
authors.forename: Abderrahmane
authors.initials: A
authors.lastname: Bengrine
authors.forename: Olivier
authors.initials: O
authors.lastname: Godefroy
authors.forename: Gary
authors.initials: G
authors.lastname: Baumbach
authors.forename: Henri
authors.initials: H
authors.lastname: Sevestre
authors.forename: Stefanie M
authors.initials: SM
authors.lastname: Bode-Boeger
authors.forename: Jan T
authors.initials: JT
authors.lastname: Kielstein
authors.forename: Ziad A
authors.initials: ZA
authors.lastname: Massy
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Chillon
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood; D001160:Arterioles / Q000378:metabolism / Q000503:physiopathology; D015153:Blotting, Western; D051242:Caveolin 1 / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects; D002561:Cerebrovascular Disorders / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology* / Q000648:ultrastructure; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009392:Nephrectomy; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D010766:Phosphorylation; D010841:Pia Mater / Q000098:blood supply*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; C495541:Cav1 protein, mouse; D051242:Caveolin 1; D018836:Inflammation Mediators; D047495:PPAR gamma; D019010:Vascular Cell Adhesion Molecule-1; D014665:Vasodilator Agents; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C515854:Rock1 protein, mouse; C515855:Rock2 protein, mouse; D054460:rho-Associated Kinases