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Downregulation of Renal G Protein–Coupled Receptor Kinase Type 4 Expression via Ultrasound‐Targeted Microbubble Destruction Lowers Blood Pressure in Spontaneously Hypertensive Rats...
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| Zeitschriftentitel: | Journal of the American Heart Association |
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| Personen und Körperschaften: | , , , , , , , , , |
| In: | Journal of the American Heart Association, 5, 2016, 10 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Ovid Technologies (Wolters Kluwer Health)
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| Schlagwörter: |
| Zusammenfassung: | <jats:sec xml:lang="en"> <jats:title>Background</jats:title> <jats:p xml:lang="en"> G protein–coupled receptor kinase type 4 ( <jats:styled-content style="fixed-case">GRK</jats:styled-content> 4) plays a vital role in the long‐term control of blood pressure (BP) and sodium excretion by regulating renal G protein–coupled receptor phosphorylation, including dopamine type 1 receptor (D <jats:sub>1</jats:sub> R). Ultrasound‐targeted microbubble destruction ( <jats:styled-content style="fixed-case">UTMD</jats:styled-content> ) is a promising method for gene delivery. Whether this method can deliver <jats:styled-content style="fixed-case">GRK</jats:styled-content> 4 small interfering RNA (si <jats:styled-content style="fixed-case">RNA)</jats:styled-content> and lower BP is not known. </jats:p> </jats:sec> <jats:sec xml:lang="en"> <jats:title>Methods and Results</jats:title> <jats:p xml:lang="en"> BP, 24‐hour sodium excretion, and urine volume were measured after <jats:styled-content style="fixed-case">UTMD</jats:styled-content> ‐targeted <jats:styled-content style="fixed-case">GRK</jats:styled-content> 4 si <jats:styled-content style="fixed-case">RNA</jats:styled-content> delivery to the kidney in spontaneously hypertensive rats. The expression levels of <jats:styled-content style="fixed-case">GRK</jats:styled-content> 4 and D <jats:sub>1</jats:sub> R were determined by immunoblotting. The phosphorylation of D <jats:sub>1</jats:sub> R was investigated using immunoprecipitation. The present study revealed that <jats:styled-content style="fixed-case">UTMD</jats:styled-content> ‐mediated renal <jats:styled-content style="fixed-case">GRK</jats:styled-content> 4 si <jats:styled-content style="fixed-case">RNA</jats:styled-content> delivery efficiently reduced <jats:styled-content style="fixed-case">GRK</jats:styled-content> 4 expression and lowered BP in spontaneously hypertensive rats, accompanied by increased sodium excretion. The increased sodium excretion might be accounted for by the <jats:styled-content style="fixed-case">UTMD</jats:styled-content> regulation of D <jats:sub>1</jats:sub> R phosphorylation and function in spontaneously hypertensive rats. Further analysis showed that, although <jats:styled-content style="fixed-case">UTMD</jats:styled-content> had no effect on D <jats:sub>1</jats:sub> R expression, it reduced D <jats:sub>1</jats:sub> R phosphorylation in spontaneously hypertensive rats kidneys and consequently increased D <jats:sub>1</jats:sub> R‐mediated natriuresis and diuresis. </jats:p> </jats:sec> <jats:sec xml:lang="en"> <jats:title>Conclusions</jats:title> <jats:p xml:lang="en"> Taken together, these study results indicate that <jats:styled-content style="fixed-case">UTMD</jats:styled-content> ‐targeted <jats:styled-content style="fixed-case">GRK</jats:styled-content> 4 si <jats:styled-content style="fixed-case">RNA</jats:styled-content> delivery to the kidney effectively reduces D <jats:sub>1</jats:sub> R phosphorylation by inhibiting renal <jats:styled-content style="fixed-case">GRK</jats:styled-content> 4 expression, improving D <jats:sub>1</jats:sub> R‐mediated natriuresis and diuresis, and lowering BP, which may provide a promising novel strategy for gene therapy for hypertension. </jats:p> </jats:sec> |
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| ISSN: |
2047-9980
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| DOI: | 10.1161/jaha.116.004028 |