title: No development of hypertension in the hyperuricemic liver-Glut9 knockout mouse.
abstract: Urate is the metabolic end point of purines in humans. Although supra-physiological plasma urate levels are associated with obesity, insulin resistance, dyslipidemia, and hypertension, a causative role is debated. We previously established a mouse model of hyperuricemia by liver-specific deletion of Glut9, a urate transporter that provides urate to the hepatocyte enzyme uricase. These LG9 knockout mice show mild hyperuricemia (120 μmol/l), which can be further increased by the urate precursor inosine. Here, we explored the role of progressive hyperuricemia on the cardiovascular function. Arterial blood pressure and heart rate were periodically measured by telemetry over 6 months in LG9 knockout mice supplemented with incremental amounts of inosine in a normal chow diet. This long-term inosine treatment elicited a progressive increase in uricemia up to 300 μmol/l; however, it did not modify heart rate or mean arterial blood pressure in LG9 knockout compared with control mice. Inosine treatment did not alter cardiac morphology or function measured by ultrasound echocardiography. However, it did induce mild renal dysfunction as revealed by higher plasma creatinine levels, lower glomerular filtration rate, and histological signs of chronic inflammation and fibrosis. Thus, in LG9 knockout mice, inosine-induced hyperuricemia was not associated with hypertension despite partial renal deficiency. This does not support a direct role of urate in the control of blood pressure.
authors.affiliation: 1] Mouse Metabolic Facility, University of Lausanne, Lausanne, Switzerland [2] Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Frederic
authors.initials: F
authors.lastname: Preitner
authors.affiliation: 1] Mouse Metabolic Facility, University of Lausanne, Lausanne, Switzerland [2] Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Anabela
authors.initials: A
authors.lastname: Pimentel
authors.affiliation: 1] Mouse Metabolic Facility, University of Lausanne, Lausanne, Switzerland [2] Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Salima
authors.initials: S
authors.lastname: Metref
authors.affiliation: Cardiovascular Assessment Facility, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Corinne
authors.initials: C
authors.lastname: Berthonneche
authors.affiliation: Cardiovascular Assessment Facility, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Sarre
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Moret
authors.affiliation: Institute of Pathology, and Mouse Pathology Facility, University of Lausanne, Lausanne, Switzerland.
authors.forename: Samuel
authors.initials: S
authors.lastname: Rotman
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Centeno
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Firsov
authors.affiliation: 1] Mouse Metabolic Facility, University of Lausanne, Lausanne, Switzerland [2] Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Bernard
authors.initials: B
authors.lastname: Thorens
mesh_terms: D000818:Animals; D001794:Blood Pressure; D004195:Disease Models, Animal; D004452:Echocardiography; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics*; D006339:Heart Rate; D033461:Hyperuricemia / Q000000981:diagnostic imaging / Q000209:etiology / Q000503:physiopathology*; D007288:Inosine; D007668:Kidney / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D051246:Glucose Transport Proteins, Facilitative; C498775:Slc2a9 protein, mouse; D007288:Inosine