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.
journal_name
Atherosclerosisjournal_title
Atherosclerosisauthors
Berger JM,Vaillant N,Le May C,Calderon C,Brégeon J,Prieur X,Hadchouel J,Loirand G,Cariou Bdoi
10.1016/j.atherosclerosis.2015.01.012subject
Has Abstractpub_date
2015-03-01 00:00:00pages
252-9issue
1eissn
0021-9150issn
1879-1484pii
S0021-9150(15)00046-5journal_volume
239pub_type
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