title: Inhibition of renal caveolin-1 reduces natriuresis and produces hypertension in sodium-loaded rats.
abstract: Renal dopamine receptor function and ion transport inhibition are impaired in essential hypertension. We recently reported that caveolin-1 (CAV1) and lipid rafts are necessary for normal D(1)-like receptor-dependent internalization of Na-K-ATPase in human proximal tubule cells. We now hypothesize that CAV1 is necessary for the regulation of urine sodium (Na(+)) excretion (U(Na)V) and mean arterial blood pressure (MAP) in vivo. Acute renal interstitial (RI) infusion into Sprague-Dawley rats of 1 μg·kg⁻¹·min⁻¹ fenoldopam (FEN; D(1)-like receptor agonist) caused a 0.46 ± 0.15-μmol/min increase in U(Na)V (over baseline of 0.29 ± 0.04 μmol/min; P < 0.01). This increase was seen in Na(+)-loaded rats, but not in those under a normal-sodium load. Coinfusion with β-methyl cyclodextrin (βMCD; lipid raft disrupter, 200 μg·kg⁻¹·min⁻¹) completely blocked this FEN-induced natriuresis (P < 0.001). Long-term (3 day) lipid raft disruption via continuous RI infusion of 80 μg·kg⁻¹·min⁻¹ βMCD decreased renal cortical CAV1 expression (47.3 ± 6.4%; P < 0.01) and increased MAP (32.4 ± 6.6 mmHg; P < 0.001) compared with vehicle-infused animals. To determine whether the MAP rise was due to a CAV1-dependent lipid raft-mediated disruption, Na(+)-loaded rats were given a bolus RI infusion of CAV1 siRNA. Two days postinfusion, cortical CAV1 expression was decreased by 73.6 ± 8.2% (P < 0.001) and the animals showed an increase in MAP by 17.4 ± 2.9 mmHg (P < 0.01) compared with animals receiving scrambled control siRNA. In summary, acute kidney-specific lipid raft disruption decreases CAV1 expression and blocks D(1)-like receptor-induced natriuresis. Furthermore, chronic disruption of lipid rafts or CAV1 protein expression in the kidney induces hypertension.
authors.affiliation: Department of Pathology, The Univ. of Virginia, Charlottesville, VA 22908, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Gildea
authors.forename: Brandon A
authors.initials: BA
authors.lastname: Kemp
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Howell
authors.forename: Robert E
authors.initials: RE
authors.lastname: Van Sciver
authors.forename: Robert M
authors.initials: RM
authors.lastname: Carey
authors.forename: Robin A
authors.initials: RA
authors.lastname: Felder
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D047468:Immunoprecipitation; D007668:Kidney / Q000378:metabolism* / Q000503:physiopathology; D009318:Natriuresis / Q000502:physiology*; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D012982:Sodium, Dietary / Q000378:metabolism* / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
chemical_list: D051242:Caveolin 1; D034741:RNA, Small Interfering; D012982:Sodium, Dietary; D000254:Sodium-Potassium-Exchanging ATPase