title: PCSK9-deficiency does not alter blood pressure and sodium balance in mouse models of hypertension.
abstract: OBJECTIVE
  Proprotein convertase subtilisin/kexin type 9 (PCSK9) is highly expressed in the kidney, where its function remains unclear. In vitro data suggested that PCSK9 could impair the trafficking of the epithelial Na channel (ENaC). Here, we aimed at determining the consequences of PCSK9-deficiency on blood pressure, sodium balance and ENaC function in vivo in mice.
  
  
  METHODS
  Blood pressure was measured using non-invasive tail-cuff system or radiotelemetry under basal conditions in male and female PCSK9(+/+) and PCSK9(-/-) mice, as well as in models of hypertension: l-NAME (2 mg/kg/day), angiotensin II (1 mg/kg/day) and deoxycorticosterone acetate (DOCA)-salt in male mice only. Plasma and urine electrolytes (Na(+), K(+), Cl(-)) were collected under basal conditions, after DOCA-salt and amiloride treatment. Renal expression of ENaC subunits was assessed by western blotting.
  
  
  RESULTS
  PCSK9-deficiency did not alter both basal blood pressure and its increase in salt-insensitive (l-NAME) and salt-sensitive (Ang-II and DOCA-salt) hypertension models. Plasma PCSK9 concentrations were increased by 2.8 fold in DOCA-salt-induced hypertension. The relative expression of the cleaved, active, 30-kDa αENaC subunit was significantly increased by 32% in kidneys of PCSK9(-/-) mice under basal, but not under high-Na(+) diet or DOCA-salt conditions. Amiloride increased urinary Na(+) excretion to similar level in both genotypes, indicating that ENaC activity was not affected by PCSK9-deficiency.
  
  
  CONCLUSIONS
  Despite an increase of cleaved αENaC under basal condition, PCSK9(-/-) mice display normal sodium balance and blood pressure regulation. Altogether, these data are reassuring regarding the development of PCSK9 inhibitors in hypercholesterolemia.
authors.affiliation: INSERM, UMR1087-CNRS UMR6291, l'Institut du Thorax, F-44000 Nantes, France.
authors.forename: Jean-Mathieu
authors.initials: JM
authors.lastname: Berger
authors.affiliation: INSERM, UMR1087-CNRS UMR6291, l'Institut du Thorax, F-44000 Nantes, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Vaillant
authors.affiliation: INSERM, UMR1087-CNRS UMR6291, l'Institut du Thorax, F-44000 Nantes, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Le May
authors.affiliation: INSERM UMR970-Paris Cardiovascular Research Center, F-75015 Paris, France; University Paris-Descartes, Sorbonne Paris Cité, Faculty of Medicine, Paris, France.
authors.forename: Carolina
authors.initials: C
authors.lastname: Calderon
authors.affiliation: INSERM, UMR1087-CNRS UMR6291, l'Institut du Thorax, F-44000 Nantes, France.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Brégeon
authors.affiliation: INSERM, UMR1087-CNRS UMR6291, l'Institut du Thorax, F-44000 Nantes, France; Université de Nantes, Institut du Thorax, F-44000 Nantes, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Prieur
authors.affiliation: INSERM UMR970-Paris Cardiovascular Research Center, F-75015 Paris, France; University Paris-Descartes, Sorbonne Paris Cité, Faculty of Medicine, Paris, France.
authors.forename: Juliette
authors.initials: J
authors.lastname: Hadchouel
authors.affiliation: INSERM, UMR1087-CNRS UMR6291, l'Institut du Thorax, F-44000 Nantes, France.
authors.forename: Gervaise
authors.initials: G
authors.lastname: Loirand
authors.affiliation: INSERM, UMR1087-CNRS UMR6291, l'Institut du Thorax, F-44000 Nantes, France; Université de Nantes, Institut du Thorax, F-44000 Nantes, France; Department of Endocrinology, University Hospital of Nantes, F-44000 Nantes, France. Electronic address: bertrand.cariou@univ-nantes.fr.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Cariou
mesh_terms: D000584:Amiloride / Q000737:chemistry; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001158:Arteries / Q000473:pathology; D001794:Blood Pressure; D001795:Blood Pressure Determination; D004195:Disease Models, Animal; D053503:Epithelial Sodium Channels / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006973:Hypertension / Q000097:blood* / Q000235:genetics; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000737:chemistry; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000097:blood / Q000172:deficiency*; D012697:Serine Endopeptidases / Q000097:blood / Q000172:deficiency*; D012964:Sodium / Q000097:blood / Q000652:urine; D017673:Sodium Chloride, Dietary / Q000494:pharmacology
chemical_list: D053503:Epithelial Sodium Channels; C507047:Scnn1a protein, mouse; D017673:Sodium Chloride, Dietary; D000804:Angiotensin II; D000584:Amiloride; D012964:Sodium; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D019331:NG-Nitroarginine Methyl Ester
keywords: Angiotensin II; DOCA-SALT; ENaC; Natriuresis