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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

BACKGROUND: G protein–coupled receptor kinase type 4 (GRK4) 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(1)R). Ultrasound‐targeted microbubble destruction...

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Autores principales: Huang, Hefei, Li, Xiaolong, Zheng, Shuo, Chen, Yue, Chen, Caiyu, Wang, Jialiang, Tong, Haipeng, Zhou, Lin, Yang, Jian, Zeng, Chunyu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121504/
https://www.ncbi.nlm.nih.gov/pubmed/27792639
http://dx.doi.org/10.1161/JAHA.116.004028
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author Huang, Hefei
Li, Xiaolong
Zheng, Shuo
Chen, Yue
Chen, Caiyu
Wang, Jialiang
Tong, Haipeng
Zhou, Lin
Yang, Jian
Zeng, Chunyu
author_facet Huang, Hefei
Li, Xiaolong
Zheng, Shuo
Chen, Yue
Chen, Caiyu
Wang, Jialiang
Tong, Haipeng
Zhou, Lin
Yang, Jian
Zeng, Chunyu
author_sort Huang, Hefei
collection PubMed
description BACKGROUND: G protein–coupled receptor kinase type 4 (GRK4) 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(1)R). Ultrasound‐targeted microbubble destruction (UTMD) is a promising method for gene delivery. Whether this method can deliver GRK4 small interfering RNA (siRNA) and lower BP is not known. METHODS AND RESULTS: BP, 24‐hour sodium excretion, and urine volume were measured after UTMD‐targeted GRK4 siRNA delivery to the kidney in spontaneously hypertensive rats. The expression levels of GRK4 and D(1)R were determined by immunoblotting. The phosphorylation of D(1)R was investigated using immunoprecipitation. The present study revealed that UTMD‐mediated renal GRK4 siRNA delivery efficiently reduced GRK4 expression and lowered BP in spontaneously hypertensive rats, accompanied by increased sodium excretion. The increased sodium excretion might be accounted for by the UTMD regulation of D(1)R phosphorylation and function in spontaneously hypertensive rats. Further analysis showed that, although UTMD had no effect on D(1)R expression, it reduced D(1)R phosphorylation in spontaneously hypertensive rats kidneys and consequently increased D(1)R‐mediated natriuresis and diuresis. CONCLUSIONS: Taken together, these study results indicate that UTMD‐targeted GRK4 siRNA delivery to the kidney effectively reduces D(1)R phosphorylation by inhibiting renal GRK4 expression, improving D(1)R‐mediated natriuresis and diuresis, and lowering BP, which may provide a promising novel strategy for gene therapy for hypertension.
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spelling pubmed-51215042016-12-06 Downregulation of Renal G Protein–Coupled Receptor Kinase Type 4 Expression via Ultrasound‐Targeted Microbubble Destruction Lowers Blood Pressure in Spontaneously Hypertensive Rats Huang, Hefei Li, Xiaolong Zheng, Shuo Chen, Yue Chen, Caiyu Wang, Jialiang Tong, Haipeng Zhou, Lin Yang, Jian Zeng, Chunyu J Am Heart Assoc Original Research BACKGROUND: G protein–coupled receptor kinase type 4 (GRK4) 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(1)R). Ultrasound‐targeted microbubble destruction (UTMD) is a promising method for gene delivery. Whether this method can deliver GRK4 small interfering RNA (siRNA) and lower BP is not known. METHODS AND RESULTS: BP, 24‐hour sodium excretion, and urine volume were measured after UTMD‐targeted GRK4 siRNA delivery to the kidney in spontaneously hypertensive rats. The expression levels of GRK4 and D(1)R were determined by immunoblotting. The phosphorylation of D(1)R was investigated using immunoprecipitation. The present study revealed that UTMD‐mediated renal GRK4 siRNA delivery efficiently reduced GRK4 expression and lowered BP in spontaneously hypertensive rats, accompanied by increased sodium excretion. The increased sodium excretion might be accounted for by the UTMD regulation of D(1)R phosphorylation and function in spontaneously hypertensive rats. Further analysis showed that, although UTMD had no effect on D(1)R expression, it reduced D(1)R phosphorylation in spontaneously hypertensive rats kidneys and consequently increased D(1)R‐mediated natriuresis and diuresis. CONCLUSIONS: Taken together, these study results indicate that UTMD‐targeted GRK4 siRNA delivery to the kidney effectively reduces D(1)R phosphorylation by inhibiting renal GRK4 expression, improving D(1)R‐mediated natriuresis and diuresis, and lowering BP, which may provide a promising novel strategy for gene therapy for hypertension. John Wiley and Sons Inc. 2016-10-06 /pmc/articles/PMC5121504/ /pubmed/27792639 http://dx.doi.org/10.1161/JAHA.116.004028 Text en © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Research
Huang, Hefei
Li, Xiaolong
Zheng, Shuo
Chen, Yue
Chen, Caiyu
Wang, Jialiang
Tong, Haipeng
Zhou, Lin
Yang, Jian
Zeng, Chunyu
Downregulation of Renal G Protein–Coupled Receptor Kinase Type 4 Expression via Ultrasound‐Targeted Microbubble Destruction Lowers Blood Pressure in Spontaneously Hypertensive Rats
title Downregulation of Renal G Protein–Coupled Receptor Kinase Type 4 Expression via Ultrasound‐Targeted Microbubble Destruction Lowers Blood Pressure in Spontaneously Hypertensive Rats
title_full Downregulation of Renal G Protein–Coupled Receptor Kinase Type 4 Expression via Ultrasound‐Targeted Microbubble Destruction Lowers Blood Pressure in Spontaneously Hypertensive Rats
title_fullStr Downregulation of Renal G Protein–Coupled Receptor Kinase Type 4 Expression via Ultrasound‐Targeted Microbubble Destruction Lowers Blood Pressure in Spontaneously Hypertensive Rats
title_full_unstemmed Downregulation of Renal G Protein–Coupled Receptor Kinase Type 4 Expression via Ultrasound‐Targeted Microbubble Destruction Lowers Blood Pressure in Spontaneously Hypertensive Rats
title_short Downregulation of Renal G Protein–Coupled Receptor Kinase Type 4 Expression via Ultrasound‐Targeted Microbubble Destruction Lowers Blood Pressure in Spontaneously Hypertensive Rats
title_sort downregulation of renal g protein–coupled receptor kinase type 4 expression via ultrasound‐targeted microbubble destruction lowers blood pressure in spontaneously hypertensive rats
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121504/
https://www.ncbi.nlm.nih.gov/pubmed/27792639
http://dx.doi.org/10.1161/JAHA.116.004028
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