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GRK4 hypertension

Zhengmeng Ye, Xi Lu, Yi Deng, Xinquan Wang, Shuo Zheng, Hongmei Ren, Miao Zhang, Tingting Chen, Pedro A Jose, Jian Yang, Chunyu Zeng
BACKGROUND/AIMS: Adverse environment in utero can modulate adult phenotypes including blood pressure. Fine particulate matter (PM2.5) exposure in utero causes hypertension in the offspring, but the exact mechanisms are not clear. Renal dopamine D1 receptor (D1R), regulated by G protein-coupled receptor kinase type 4 (GRK4), plays an important role in the regulation of renal sodium transport and blood pressure. In this present study, we determined if renal D1R dysfunction is involved in PM2...
2018: Cellular Physiology and Biochemistry
Melissa K Frey, Fanny Dao, Narciso Olvera, Jason A Konner, Maura N Dickler, Douglas A Levine
OBJECTIVE: Bevacizumab, a monoclonal antibody to VEGF, has shown efficacy in ovarian, cervical and endometrial cancer in addition to several other solid tumors. Serious side effects include hypertension, proteinuria, bowel perforation, and thrombosis. We tested the hypothesis that genetic variation in hypertension-associated genes is associated with bevacizumab-induced hypertension (BIH). METHODS: Patients with solid tumors treated with bevacizumab in combination with other therapy were identified from six clinical trials...
December 2017: Gynecologic Oncology
C-Q Yu, L-Q Yin, Z-T Tu, D-W Liu, W-P Luo
OBJECTIVE: Renal dopamine receptor D1 played a critical role in the regulation of body blood pressure. Under hypertension, over-phosphorylation of D1 receptor impaired its function. G protein kinase 4 (GRK4) and protein phosphatase 2A (PP2A) exerted the effect to phosphorylate and de-phosphorylate D1 receptor. A current study revealed that the inhibition of GRK4 cannot normalize the phosphorylation level of D1 receptor. Meanwhile, the PP2A was activated under hypertension, indicating abnormal de-phosphorylation function of D1 receptor, the reason for which remains unknown...
July 2017: European Review for Medical and Pharmacological Sciences
Erika S Jones, J D Spence, Adam D Mcintyre, Justus Nondi, Kennedy Gogo, Adeseye Akintunde, Daniel G Hackam, Brian L Rayner
OBJECTIVES: Black subjects tend to retain salt and water, be more sensitive to aldosterone, and have suppression of plasma renin activity. Variants of the renal sodium channel (ENaC, SCNN1B) account for approximately 6% of resistant hypertension (RHT) in Blacks; other candidate genes may be important. METHODS: Six candidate genes associated with low renin-resistant hypertension were sequenced in Black Africans from clinics in Kenya and South Africa. CYP11B2 was sequenced if the aldosterone level was high (primary aldosteronism phenotype); SCNN1B, NEDD4L, GRK4, UMOD, and NPPA genes were sequenced if the aldosterone level was low (Liddle phenotype)...
May 1, 2017: American Journal of Hypertension
Hefei Huang, Xiaolong Li, Shuo Zheng, Yue Chen, Caiyu Chen, Jialiang Wang, Haipeng Tong, Lin Zhou, Jian Yang, Chunyu Zeng
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 (D1 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...
October 6, 2016: Journal of the American Heart Association
K Chen, C Fu, C Chen, P A Jose, C Zeng
No abstract text is available yet for this article.
July 2016: Journal of the American Society of Hypertension: JASH
He Zhang, Zhao-qing Sun, Shuang-shuang Liu, Li-na Yang
The role of GRK4 and DRD1 genes in hypertension remains controversial. We performed a meta-analysis to determine whether GRK4 and DRD1 polymorphisms influence the risk of hypertension and examined the relationship between the genetic variances and the etiology of hypertension. Relevant case-control studies were retrieved by database searches and selected according to established inclusion criteria. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the associations...
2016: Clinical Interventions in Aging
Zheng Wang, Chunyu Zeng, Van Anthony M Villar, Shi-You Chen, Prasad Konkalmatt, Xiaoyan Wang, Laureano D Asico, John E Jones, Yu Yang, Hironobu Sanada, Robin A Felder, Gilbert M Eisner, Matthew R Weir, Ines Armando, Pedro A Jose
The influence of a single gene on the pathogenesis of essential hypertension may be difficult to ascertain, unless the gene interacts with other genes that are germane to blood pressure regulation. G-protein-coupled receptor kinase type 4 (GRK4) is one such gene. We have reported that the expression of its variant hGRK4γ(142V) in mice results in hypertension because of impaired dopamine D1 receptor. Signaling through dopamine D1 receptor and angiotensin II type I receptor (AT1R) reciprocally modulates renal sodium excretion and blood pressure...
February 2016: Hypertension
Samantha J Allen, Gopal Parthasarathy, Paul L Darke, Ronald E Diehl, Rachael E Ford, Dawn L Hall, Scott A Johnson, John C Reid, Keith W Rickert, Jennifer M Shipman, Stephen M Soisson, Paul Zuck, Sanjeev K Munshi, Kevin J Lumb
G-protein-coupled receptor (GPCR) kinases (GRKs) bind to and phosphorylate GPCRs, initiating the process of GPCR desensitization and internalization. GRK4 is implicated in the regulation of blood pressure, and three GRK4 polymorphisms (R65L, A142V, and A486V) are associated with hypertension. Here, we describe the 2.6 Å structure of human GRK4α A486V crystallized in the presence of 5'-adenylyl β,γ-imidodiphosphate. The structure of GRK4α is similar to other GRKs, although slight differences exist within the RGS homology (RH) bundle subdomain, substrate-binding site, and kinase C-tail...
August 14, 2015: Journal of Biological Chemistry
Yingzi Zhao, Paul M Vanhoutte, Susan W S Leung
BACKGROUND AND PURPOSE: In the aorta of adult spontaneously hypertensive (SHR), but not in that of normotensive Wistar-Kyoto (WKY), rats, previous exposure to phenylephrine inhibits subsequent contractions to PGE2 . The present experiments were designed to examine the mechanism(s) underlying this inhibition. EXPERIMENTAL APPROACH: Isometric tension was measured in isolated rings of SHR and WKY aortae. Gene expression and protein presence were measured by quantitative real-time PCR and Western blotting respectively...
July 2015: British Journal of Pharmacology
Brian Rayner, Raj Ramesar
Salt sensitivity is probably caused by either a hereditary or acquired defect of salt excretion by the kidney, and it is reasonable to consider that this is the basis for differences in hypertension between black and white people. Dopamine acts in an autocrine/paracrine fashion to promote natriuresis in the proximal tubule and thick ascending loop of Henle. G-protein receptor kinases (or GRKs) are serine and threonine kinases that phosphorylate G protein-coupled receptors in response to agonist stimulation and uncouple the dopamine receptor from its G protein...
2015: International Journal of Molecular Sciences
H Sanada, M Yoneda, J Yatabe, S M Williams, J Bartlett, M J White, L N Gordon, R A Felder, G M Eisner, I Armando, P A Jose
Non-synonymous GRK4 variants, R65L, A142V and A486V, are associated with essential hypertension in diverse populations. This study replicated the association of GRK4 variants, including GRK4(142V), with human essential hypertension in a Japanese population (n=588; hypertensive, n=486 normotensive controls) and determined whether the presence of GRK4 variants predicted the blood pressure (BP) response to angiotensin receptor blockers (ARBs) in patients with essential hypertension. We analyzed 829 patients and compared the response to ARBs between individuals with no GRK4 variants (n=136) and those with variants at one or any of the three loci (n=693)...
February 2016: Pharmacogenomics Journal
Xinquan Wang, Hao Luo, Caiyu Chen, Ken Chen, Jialiang Wang, Yue Cai, Shuo Zheng, Xiaoli Yang, Lin Zhou, Pedro A Jose, Chunyu Zeng
Adverse environment in early life can modulate the adult phenotype, including blood pressure. Lipopolysaccharide (LPS) exposure in utero results in increased blood pressure in the offspring, but the exact mechanisms are not clear. Studies have shown that the renal dopamine D1 receptor (D1R) plays an important role in maintaining sodium homeostasis and normal blood pressure; dysfunction of D1R is associated with oxidative stress and hypertension. In this study, we determined if dysfunction of the renal D1R is involved in fetal-programmed hypertension, and if oxidative stress contributes to this process...
November 2014: Free Radical Biology & Medicine
Miles D Thompson, David E C Cole, Pedro A Jose, Peter Chidiac
The identification and characterization of the genes encoding G protein-coupled receptors (GPCRs) and the proteins necessary for the processes of ligand binding, GPCR activation, inactivation, and receptor trafficking to the membrane are discussed in the context of human genetic disease. In addition to functional GPCR variants, the identification of genetic disruptions affecting proteins necessary to GPCR functions have provided insights into the function of these pathways. Gsα and Gβ subunit polymorphisms have been found to result in complex phenotypes...
2014: Methods in Molecular Biology
Ines Armando, Prasad Konkalmatt, Robin A Felder, Pedro A Jose
Salt sensitivity of blood pressure, whether in hypertensive or normotensive subjects, is associated with increased cardiovascular risk and overall mortality. Salt sensitivity can be treated by reducing NaCl consumption. However, decreasing salt intake in some may actually increase cardiovascular risk, including an increase in blood pressure, that is, inverse salt sensitivity. Several genes have been associated with salt sensitivity and inverse salt sensitivity. Some of these genes encode proteins expressed in the kidney that are needed to excrete a sodium load, for example, dopamine receptors and their regulators, G protein-coupled receptor kinase 4 (GRK4)...
April 2015: Translational Research: the Journal of Laboratory and Clinical Medicine
May E Montasser, Lawrence C Shimmin, Dongfeng Gu, Jing Chen, Charles Gu, Tanika N Kelly, Cashell E Jaquish, Treva K Rice, Dabeeru C Rao, Jie Cao, Jichun Chen, De-PeLiu, Paul K Whelton, Lotuce Lee Hamm, Jiang He, James E Hixson
Chronic kidney disease (CKD) can be a consequence of diabetes, hypertension, immunologic disorders, and other exposures, as well as genetic factors that are still largely unknown. Glomerular filtration rate (GFR), which is widely used to measure kidney function, has a heritability ranging from 25% to 75%, but only 1.5% of this heritability is explained by genetic loci that have been identified to date. In this study we tested for associations between GFR and 234 SNPs in 26 genes from pathways of blood pressure regulation in 3,025 rural Chinese participants of the "Genetic Epidemiology Network of Salt Sensitivity" (GenSalt) study...
2014: PloS One
Ken Chen, Chunjiang Fu, Caiyu Chen, Li Liu, Hongmei Ren, Yu Han, Jian Yang, Duofen He, Lin Zhou, Zhiwei Yang, Lianfeng Zhang, Pedro A Jose, Chunyu Zeng
G-protein-coupled receptor kinase 4 (GRK4) gene variants, via impairment of renal dopamine receptor and enhancement of renin-angiotensin system functions, cause sodium retention and increase blood pressure. Whether GRK4 and the angiotensin type 1 receptor (AT(1)R) interact in the aorta is not known. We report that GRK4 is expressed in vascular smooth muscle cells of the aorta. Heterologous expression of the GRK4γ variant 142V in A10 cells increased AT(1)R protein expression and AT(1)R-mediated increase in intracellular calcium concentration...
February 2014: Hypertension
John J Gildea, Hanh T Tran, Robert E Van Sciver, Dora Bigler Wang, Julia M Carlson, Robin A Felder
The G protein-coupled receptor kinase 4 (GRK4) negatively regulates the dopaminergic system by desensitizing the dopamine-1-receptor. The expressional control of GRK4 has not been reported, but here we show that the transcription factor c-Myc binds to the promoter of GRK4 and positively regulates GRK4 protein expression in human renal proximal tubule cells (RPTCs). Addition of phorbol esters to RPTCs not only increased c-Myc binding to the GRK4 promoter but also increased both phospho-c-Myc and GRK4 expression...
May 2013: Hypertension
Van Anthony M Villar, Ines Armando, Hironobu Sanada, Lauren C Frazer, Christen M Russo, Patricia M Notario, Hewang Lee, Lauren Comisky, Holly Ann Russell, Yu Yang, Julie A Jurgens, Pedro A Jose, John E Jones
The D1 dopamine receptor (D1R) is widely expressed in the kidney and plays a crucial role in blood pressure regulation. Although much is known about D1R desensitization, especially through G-protein-coupled receptor kinase 4 (GRK4), comparatively little is known about other aspects of D1R trafficking and the proteins involved in the process. We now report the discovery of a dynamic interaction between sorting nexin 5 (SNX5), a component of the mammalian retromer, and D1R in human renal epithelial cells. We show that internalization of agonist-activated D1R is regulated by both SNX5 and GRK4, and that SNX5 is critical to the recycling of the receptor to the plasma membrane...
May 2013: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Soo Jin Yang, Seung-Tae Lee, Won Jun Kim, Se Eun Park, Sung Woo Park, Jong-Won Kim, Cheol-Young Park
Hypertension and arterial stiffness are associated with an increasing risk of diabetes and cardiovascular diseases. This study aimed to identify genetic variants affecting hypertension and arterial stiffness in diabetic subjects and to compare genetic associations with hypertension between prediabetic and diabetic subjects. A total of 1,069 participants (326 prediabetic and 743 diabetic subjects) were assessed to determine the genetic variants affecting hypertension by analyzing 52 SNPs previously reported to be associated with hypertension...
2012: Experimental Diabetes Research
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