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Papers by John jones

American Journal of Hypertension, 2005

inhibitors. Ionomycin, a Ca 2ϩ ionophore, which increased intracellular free Ca 2ϩ concentration ... more inhibitors. Ionomycin, a Ca 2ϩ ionophore, which increased intracellular free Ca 2ϩ concentration as measured by fura 2 fluorescence, and Ang II significantly increased phosphorylation of ERK1/2, p38MAPK and JNK by 8-10 fold (pϽ0.01 vs controls). FKC506 pretreatment completely abolished ionomycin-induced effects. Cyclosporine A also reduced ionomycin actions, but responses were less than those produced by FK506. Ang II-mediated actions were not influenced by calcineurin inhibitors. Total MAPK protein content was unaltered by FKC506 and cyclosporine A. These results suggest that ERK1/2, p38MAPK and JNK are potently activated by Ca 2ϩ-and Ang II-dependent signaling pathways. Whereas MAP kinase regulation by Ca 2ϩ / calmodulin is calcineurin-dependent, Ang II regulation of cardiac fibroblast MAP kinase is calcineurin-independent. Our data indicate differential activation of MAP kinases in cardiac fibroblasts. Supported by Fujisawa Canada Inc.

Hypertension research : official journal of the Japanese Society of Hypertension, Jan 26, 2015

Humans have dopamine D5 receptors (hD5R) with single-nucleotide polymorphisms and a diminished fu... more Humans have dopamine D5 receptors (hD5R) with single-nucleotide polymorphisms and a diminished function. We generated hD5(F173L) cDNA that has a decreased response to D5R agonist-mediated increase in cAMP production and increased production of reactive oxygen species, relative to wild-type hD5R (hD5(WT)) cDNA expressed in Chinese hamster ovary cells. To investigate the role of hD5(F173L) in the pathogenesis of salt-sensitive hypertension, we generated transgenic mice overexpressing hD5(F173L) or hD5(WT) and fed them normal (0.8% NaCl) or high (4% NaCl) salt diet. On normal salt diet, the blood pressure, and renal NADPH oxidase activity and angiotensin type 1 receptor (AT1R) expression were higher in hD5(F173L) than hD5(WT) transgenic mice. After 2 weeks on high salt diet, the blood pressure and renal NADPH oxidase activity, but not AT1R expression, were increased in hD5(F173L) but not in hD5(WT) transgenic mice. Candesartan, an AT1R antagonist, decreased the blood pressure and NADPH...

International Journal of Pediatrics, 2012

Events that occur in the early fetal environment have been linked to long-term health and lifespa... more Events that occur in the early fetal environment have been linked to long-term health and lifespan consequences in the adult. Intrauterine growth restriction (IUGR), which may occur as a result of nutrient insufficiency, exposure to hormones, or disruptions in placental structure or function, may induce the fetus to alter its developmental program in order to adapt to the new conditions. IUGR may result in a decrease in the expression of genes that are responsible for nephrogenesis as nutrients are rerouted to the development of more essential organs. Fetal survival under these conditions often results in low birth weight and a deficit in nephron endowment, which are associated with hypertension in adults. Interestingly, male IUGR offspring appear to be more severely affected than females, suggesting that sex hormones may be involved. The processes of fetal programming of hypertension are complex, and we are only beginning to understand the underlying mechanisms.

American journal of physiology. Regulatory, integrative and comparative physiology, Jan 15, 2014

Dopamine-mediated regulation of Na(+)-K(+)-ATPase activity in the posterior gills of some crustac... more Dopamine-mediated regulation of Na(+)-K(+)-ATPase activity in the posterior gills of some crustaceans has been reported to be involved in osmoregulation. The dopamine receptors of invertebrates are classified into three groups based on their structure and pharmacology: D1- and D2-like receptors and a distinct invertebrate receptor subtype (INDR). We tested the hypothesis that a D1-like receptor is expressed in the blue crab Callinectes sapidus and regulates Na(+)-K(+)-ATPase activity. RT-PCR, using degenerate primers, showed the presence of D1βR mRNA in the posterior gill. The blue crab posterior gills showed positive immunostaining for a dopamine D5 receptor (D5R or D1βR) antibody in the basolateral membrane and cytoplasm. Confocal microscopy showed colocalization of Na(+)-K(+)-ATPase and D1βR in the basolateral membrane. To determine the effect of D1-like receptor stimulation on Na(+)-K(+)-ATPase activity, intact crabs acclimated to low salinity for 6 days were given an intracardi...

Kidney International, 2004

D 1 dopamine receptor signaling involves caveolin-2 in HEK-293 cells. Background. Dopamine recept... more D 1 dopamine receptor signaling involves caveolin-2 in HEK-293 cells. Background. Dopamine receptors in the kidney, especially those belonging to the D 1-like receptor family, are important in the regulation of renal function and blood pressure. Because of increasing evidence that G protein-coupled receptors (GPCRs) are associated with caveolae and lipid rafts, we tested the hypothesis that the D 1 dopamine receptor (D 1 R) and signaling molecules are regulated by caveolin in caveolae or lipid rafts. Methods. Six experimental approaches were used: (1) construction of tagged human D 1 Rs (hD 1 Rs) and transfectants; (2) cell culture [human embryonic kidney (HEK)-293 and immortalized rat renal proximal tubule cells] and biotinylation; (3) cell fractionation by sucrose gradient centrifugation; (4) immunoprecipitation and immunoblotting; (5) immunofluorescence and confocal microscopy; and (6) adenylyl cyclase assays. Results. hD 1 Rs, heterologously expressed in HEK-293 cells, formed protein species with molecular mass ranging from 50 to 250 kD, and were localized in lipid rafts and nonraft plasma membranes. The hD 1 Rs cofractionated with caveolin-2, G protein subunits, and several signaling molecules. Both exogenously expressed hD 1 Rs and endogenously expressed rat D 1 Rs colocalized and coimmunoprecipitated with caveolin-2. A D 1 R agonist (fenoldopam) increased the amount of caveolin-2b associated with hD 1 Rs and activated adenylyl cyclase to a greater extent in lipid rafts than in nonraft plasma membranes. Reduction in the expression of caveolin-2 with antisense oligonucleotides attenuated the stimulatory effect of fenoldopam on cyclic adenosine monophosphate (cAMP) accumulation. Conclusion. The majority of hD 1 Rs are distributed in lipid rafts. Heterologously and endogenously expressed D 1 Rs in renal cells are associated with and regulated by caveolin-2. Lipid rafts are membrane microdomains composed of sphingolipids, cholesterol, glycolipids, and specific pro-Key words: D 1 dopamine receptor, caveolin-2, flotillin, renal proximal tubule, cAMP.

Journal of Clinical Investigation, 2008

Hypertension is a multigenic disorder in which abnormal counterregulation between dopamine and An... more Hypertension is a multigenic disorder in which abnormal counterregulation between dopamine and Ang II plays a role. Recent studies suggest that this counterregulation results, at least in part, from regulation of the expression of both the antihypertensive dopamine 5 receptor (D 5 R) and the prohypertensive Ang II type 1 receptor (AT 1 R). In this report, we investigated the in vivo and in vitro interaction between these GPCRs. Disruption of the gene encoding D 5 R in mice increased both blood pressure and AT 1 R protein expression, and the increase in blood pressure was reversed by AT 1 R blockade. Activation of D 5 R increased the degradation of glycosylated AT 1 R in proteasomes in HEK cells and human renal proximal tubule cells heterologously and endogenously expressing human AT 1 R and D 5 R. Confocal microscopy, Förster/fluorescence resonance energy transfer microscopy, and fluorescence lifetime imaging microscopy revealed that activation of D 5 R initiated ubiquitination of the glycosylated AT 1 R at the plasma membrane. The regulated degradation of AT 1 R via a ubiquitin/proteasome pathway by activation of D 5 R provides what we believe to be a novel mechanism whereby blood pressure can be regulated by the interaction of 2 counterregulatory GPCRs. Our results therefore suggest that treatments for hypertension might be optimized by designing compounds that can target the AT 1 R and the D 5 R.

Hypertension, 2006

Dopamine receptors are important in systemic blood pressure regulation. D 4 receptors are express... more Dopamine receptors are important in systemic blood pressure regulation. D 4 receptors are expressed in the kidney and brain, but their role in cardiovascular regulation is unknown. In pentobarbital-anesthetized mice, systolic and diastolic blood pressures were elevated in sixth-generation D 4 receptor–deficient (D 4 −/− ) mice and in tenth-generation D 4 −/− mice compared with D 4 wild-type (D 4 +/+ ) littermates. The conscious blood pressures measured via a chronic arterial (femoral) catheter or telemetry (carotid) were also higher in D 4 −/− mice than in D 4 littermates. Basal renal and plasma renin concentrations were similar in the 2 mouse strains. The protein expression of angiotensin II type 1 receptor was increased in homogenates of kidney (330±53%, n=5) and brain (272±69%, n=5) of D 4 −/− mice relative to D 4 +/+ mice (kidney: 100±12%, n=5; brain: 100±32%, n=5). The expression of the receptor in renal membrane was also increased in D 4 −/− mice (289±28%, n=8) relative to D 4...

Circulation Research, 2006

The dopaminergic and renin angiotensin systems interact to regulate blood pressure. Disruption of... more The dopaminergic and renin angiotensin systems interact to regulate blood pressure. Disruption of the D 3 dopamine receptor gene in mice produces renin-dependent hypertension. In rats, D 2 -like receptors reduce angiotensin II binding sites in renal proximal tubules (RPTs). Because the major D 2 -like receptor in RPTs is the D 3 receptor, we examined whether D 3 receptors regulate angiotensin II type 1 (AT 1 ) receptors in rat RPT cells. The effect of D 3 receptors on AT 1 receptors was studied in vitro and in vivo. The D 3 receptor agonist PD128907 decreased AT 1 receptor protein and mRNA in WKY RPT cells and increased it in SHR cells. PD128907 increased D 3 receptors in WKY cells but had no effect in SHR cells. D 3 /AT 1 receptors colocalized in RPT cells; D 3 receptor stimulation decreased the percent amount of D 3 receptors that coimmunoprecipitated with AT 1 receptors to a greater extent in WKY than in SHR cells. However, D 3 receptor stimulation did not change the percent amou...

Hypertension, Jan 14, 2015

The influence of a single gene on the pathogenesis of essential hypertension may be difficult to ... more 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. Here, we demonstrate the ability of the hGRK4γ(142V) to increase the expression and activity of the AT1R. We show that hGRK4γ(142V) phosphorylates histone deacetylase type 1 and promotes its nuclear export to the cytoplasm, resulting in increased AT1R expression and greater pressor response to angiotensin II. AT1R blockade and the deletion of the Agtr1a gene normalize the hypertension in hGRK4γ(142V) mice. These findings illustrate the unique ...

Genomics and Molecular Genetics of Plant-Nematode Interactions, 2011

... expression patterns in C. elegans and are thought to have a different role in this ... Reavy ... more ... expression patterns in C. elegans and are thought to have a different role in this ... Reavy B, Smant G, Prior AE (2004) Glutathione peroxidases of the potato cyst nematode Globodera rostochiensis ... 16:713 Kay S, Bonas U (2009) How Xanthomonas type III effectors manipulate the ...

Volume 9: Micro- and Nano-Systems Engineering and Packaging, Parts A and B, 2012

ABSTRACT Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Associat... more ABSTRACT Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

Toxicology Letters, 2007

Three human monocytic cell lines (MUTZ-3, THP-1, U-937) have been investigated in regard to their... more Three human monocytic cell lines (MUTZ-3, THP-1, U-937) have been investigated in regard to their capacity to predict the sensitization potential of a panel of strong to weak sensitizers. Cells were treated 24 h with the sensitizers and collected for analysis. Expression of several markers (CD86, CD54, IL-1beta, IL-8) was monitored at the protein (flow cytometry) and/or at the mRNA (Q-PCR) level. Our data show that despite differences all models are comparably responsive to sensitizers. The data presented are also compared with those generated with the MUTZ-3-DC (differentiated MUTZ-3) model.

Quaternary Science Reviews, 2009

... adapted in a variety of ways over the Holocene to changing Neotropical wetlands ... in Mesoam... more ... adapted in a variety of ways over the Holocene to changing Neotropical wetlands ... in Mesoamerican wetlands may have been another form of ancient intensive agriculture, namely canal ... range of ecosystems and human response in the Maya Lowlands during the Late Holocene. ...

Proceedings of the American Mathematical Society, 1966

Physical Review Letters, 2010

Mathematical Logic Quarterly, 1983