Pedro Jose - Academia.edu (original) (raw)
Papers by Pedro Jose
International Journal of Molecular Sciences, Aug 27, 2013
Dopamine, which is synthesized in the kidney, independent of renal nerves, plays an important rol... more Dopamine, which is synthesized in the kidney, independent of renal nerves, plays an important role in the regulation of fluid and electrolyte balance and systemic blood pressure. Lack of any of the five dopamine receptor subtypes (D1R, D2R, D3R, D4R, and D5R) results in hypertension. D1R, D2R, and D5R have been reported to be important in the maintenance of a normal redox balance. In the kidney, the antioxidant effects of these receptors are caused by direct and indirect inhibition of pro-oxidant enzymes, specifically, nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase, and stimulation of anti-oxidant enzymes, which can also indirectly inhibit NADPH oxidase activity. Thus, stimulation of the D2R increases the expression of endogenous anti-oxidants, such as Parkinson protein 7 (PARK7 or DJ-1), paraoxonase 2 (PON2), and heme oxygenase 2 (HO-2), all of which can inhibit NADPH oxidase activity. The D5R decreases NADPH oxidase activity, via the inhibition of phospholipase D2, and increases the expression of HO-1, another antioxidant. D1R inhibits NADPH oxidase activity via protein kinase A and protein kinase C cross-talk. In this review, we provide an overview of the protective roles of a specific dopamine receptor subtype on renal oxidative stress, the different mechanisms involved in this effect, and the role of oxidative stress and impairment of dopamine receptor function in the hypertension that arises from the genetic ablation of a specific dopamine receptor gene in mice.
International Journal of Molecular Sciences, 2020
The renal dopaminergic system has been identified as a modulator of sodium balance and blood pres... more The renal dopaminergic system has been identified as a modulator of sodium balance and blood pressure. According to the Centers for Disease Control and Prevention, in 2018 in the United States, almost half a million deaths included hypertension as a primary or contributing cause. Renal dopamine receptors, members of the G protein-coupled receptor family, are divided in two groups: D1-like receptors that act to keep the blood pressure in the normal range, and D2-like receptors with a variable effect on blood pressure, depending on volume status. The renal dopamine receptor function is regulated, in part, by its expression in microdomains in the plasma membrane. Lipid rafts form platforms within the plasma membrane for the organization and dynamic contact of molecules involved in numerous cellular processes such as ligand binding, membrane sorting, effector specificity, and signal transduction. Understanding all the components of lipid rafts, their interaction with renal dopamine rece...
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 1998
In vitro studies have suggested that dopamine D1- and D2-like receptors interact to inhibit renal... more In vitro studies have suggested that dopamine D1- and D2-like receptors interact to inhibit renal sodium transport. We used Z-1046, a dopamine receptor agonist with the rank-order potency D3≥ D4> D2> D5> D1, to test the hypothesis that D1- and D2-like receptors interact to inhibit renal sodium transport in vivo in anesthetized rats. Increasing doses of Z-1046, administered via the right renal artery, increased renal blood flow (RBF), urine flow, and absolute and fractional sodium excretion without affecting glomerular filtration rate. For determination of the dopamine receptor involved in the renal functional effects of Z-1046, another group of rats received Z-1046 at 2 μg ⋅ kg−1⋅ min−1( n = 10) in the presence or absence of the D2-like receptor antagonist domperidone and/or the D1-like antagonist SCH-23390. Domperidone alone had no effect but blocked the Z-1046-mediated increase in urine flow and sodium excretion; it enhanced the increase in RBF after Z-1046. SCH-23390 by ...
Hypertension (Dallas, Tex. : 1979), 2018
coding RNA (ncRNA)-mediated targeting of various genes [9] , e.g., G-protein-coupled receptor kin... more coding RNA (ncRNA)-mediated targeting of various genes [9] , e.g., G-protein-coupled receptor kinase type 4 phosphorylates histone deacetylase type 1, promoting its nuclear export to the cytoplasm, resulting in increased Angiotensin II receptor type 1 (AGTR1) expression and greater pressor response to angiotensin II [10]. This review aims to provide an overview of the likely role of ncRNAs in the development of hypertension, as well as advances in ncRNA-based diagnoses and therapeutic approaches. A better understanding of the ncRNA-based molecular mechanisms of the pathogenesis of hypertension is important for the prevention and treatment of hypertension and its complications. 2. ncRNAs Historically, protein-coding genes, with proteins as the final gene products, have been viewed to mediate the phenotype and biological function of any given cell. However, more and more recent studies have shown that ncRNAs participate in the regulation of the expression of protein-coding genes and therefore, play essential roles in many biological processes. These findings have uncovered that ncRNAs orchestrate a hidden layer of generegulation network [11]. These ncRNAs have emerged as dynamic managers that influence the interaction between DNA and the environment that characterizes epigenetics. Generally, ncRNAs are generated in the nucleus, transcribed by RNA polymerase II (RNA Pol II), giving rise to a long precursor mRNA (pre-mRNA), and the main processing mechanism for pre-mRNA transcript is processed by the spliceosome. Apart from the similarities, there are many differences between different types of ncRNAs in biogenesis and processing, which has been recently reviewed elsewhere [12]. Based on size, ncRNAs are classified by the size as the small (~20 nucleotides), intermediate (~20-200 nucleotides), or long (>200 nucleotides). Small ncRNAs (~20 nucleotides) include piwi-interacting RNAs, the largest class of ncRNAs, small interfering RNAs (siRNAs), guide RNA, and miRNAs [13]. Intermediate ncRNAs (~20-200 nucleotides) are involved in splicing during protein synthesis and include nucleolar RNAs that modify ribosome RNA, transcription start site (TSS)-associated RNAs and promoter-associated small RNAs [13]. The rest of the ncRNAs, that are greater than 200 nucleotides, have been grouped into long non-coding RNAs (lncRNAs). Unlike miRNA, lncRNAs have numerous functions in cis and in trans by regulating gene expression with transcription and translation, splicing, chromatin imprinting, and cell cycle development. lncRNAs can silence multiple genes through their interaction with chromatin, or even recruit transcriptional factors to target promoters and induce transcription, indicating that they are central to the epigenetic control of gene expression. The 3'-and 5'-ends of linear RNA transcripts can join and form a loop to make circular RNA (circRNA), a newly identified group of ncRNA, which exhibits stability and high conservation and plays a role in many biological processes [14]. The pathogenesis of hypertension entails a complex interaction of different organs and systems, including an over-activation (e.g., renin-angiotensin-aldosterone system [RAAS], central nervous system, sympathetic nervous systems, central nervous and peripheral nervous system, including renal nerves) or under-activation (e.g., parasympathetic nervous Wu et al.
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology, Jan 21, 2018
Adverse environment in utero can modulate adult phenotypes including blood pressure. Fine particu... more 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 PM2.5-induced hypertension in the offspring. Pregnant Sprague-Dawley rats were given an oropharyngeal drip of PM2.5 (1.0 mg/kg) at gestation day 8, 10, and 12. The blood pressure, 24-hour sodium excretion, and urine volume were measured in the offspring. The expression levels of GRK4 and D1R were determined by immunoblotting. The phosphorylation of D1R was investigated using immunoprecipitation. Plasma malondialdehyde and superoxide dismutase levels were also measured in the offspring. As compared with saline-treated ...
Journal of the American Heart Association, Jan 7, 2018
Epidemiological evidence supports an important association between air pollution exposure and hyp... more Epidemiological evidence supports an important association between air pollution exposure and hypertension. However, the mechanisms are not clear. Our present study found that long-term exposure to fine particulate matter (PM2.5) causes hypertension and impairs renal sodium excretion, which might be ascribed to lower D1 receptor expression and higher D1 receptor phosphorylation, accompanied with a higher G-protein-coupled receptor kinase type 4 (GRK4) expression. The in vivo results were confirmed in in vitro studies (ie, PM2.5 increased basal and decreased D1 receptor mediated inhibitory effect on Na+-K+ ATPase activity, decreased D1 receptor expression, and increased D1 receptor phosphorylation in renal proximal tubule cells). The downregulation of D1 receptor expression and function might be attributable to a higher GRK4 expression after the exposure of renal proximal tubule cells to PM2.5, because downregulation of GRK4 by small-interfering RNA reversed the D1 receptor expressio...
American Journal of Hypertension, 2003
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 ...
American Journal of Hypertension, 2005
Basal cAMP level (pmol/mg protein) was lower in SHR than in WKY (5.5Ϯ0.1 vs. 8.4Ϯ0.4, pϽ0.01, nϭ3... more Basal cAMP level (pmol/mg protein) was lower in SHR than in WKY (5.5Ϯ0.1 vs. 8.4Ϯ0.4, pϽ0.01, nϭ3) rats. Although terbutaline (10-8 M, 20 min) increased cAMP accumulation to a similar degree in WKY and SHRs (63Ϯ10% vs. 68Ϯ8%, pϾ0.05, nϭ3), it inhibited NHE3 activity to a greater extent in WKY (41Ϯ15 %) than in SHRs (32Ϯ13 %) (pϽ0.05, nϭ12). Conclusion: The lower amount of 2-AR on the cell surface of SHR IRPTCs in comparison to WKY may explain the decreased ability of 2-AR to inhibit NHE3 activity in SHRs. The inhibition of NHE3 activity by 2-AR is apparently independent of cAMP.
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...
American Journal of Hypertension, 2005
Basal cAMP level (pmol/mg protein) was lower in SHR than in WKY (5.5Ϯ0.1 vs. 8.4Ϯ0.4, pϽ0.01, nϭ3... more Basal cAMP level (pmol/mg protein) was lower in SHR than in WKY (5.5Ϯ0.1 vs. 8.4Ϯ0.4, pϽ0.01, nϭ3) rats. Although terbutaline (10-8 M, 20 min) increased cAMP accumulation to a similar degree in WKY and SHRs (63Ϯ10% vs. 68Ϯ8%, pϾ0.05, nϭ3), it inhibited NHE3 activity to a greater extent in WKY (41Ϯ15 %) than in SHRs (32Ϯ13 %) (pϽ0.05, nϭ12). Conclusion: The lower amount of 2-AR on the cell surface of SHR IRPTCs in comparison to WKY may explain the decreased ability of 2-AR to inhibit NHE3 activity in SHRs. The inhibition of NHE3 activity by 2-AR is apparently independent of cAMP.
American journal of physiology. Renal physiology, 2014
The homeostatic control of blood pressure hinges upon the delicate balance between prohypertensin... more The homeostatic control of blood pressure hinges upon the delicate balance between prohypertensinogenic and antihypertensinogenic systems. D₁-like dopamine receptors [dopamine D₁ and D₅ receptors (D₁Rs and D₅Rs, respectively)] and the α₁A-adrenergic receptor (α₁A-AR) are expressed in the renal proximal tubule and engender opposing effects on Na(+) transport, i.e., natriuresis (via D₁Rs and D5Rs) or antinatriuresis (via α₁A-ARs). We tested the hypothesis that the D₁R/D₅R regulates the α₁A-AR. D₁-like dopamine receptors coimmunoprecipitated, colocalized, and cofractionated with α₁A-ARs in lipid rafts in immortalized human renal proximal tubule cells. Long-term treatment with the D₁R/D₅R agonist fenoldopam resulted in decreased D₁R and D₅R expression but increased α₁A-AR abundance in the plasma membrane. Short-term fenoldopam treatment stimulated the translocation of Na(+)-K(+)-ATPase from the plasma membrane to the cytosol that was partially reversed by an α₁A-AR agonist, which by its...
International Journal of Molecular Sciences, 2013
Dopamine, which is synthesized in the kidney, independent of renal nerves, plays an important rol... more Dopamine, which is synthesized in the kidney, independent of renal nerves, plays an important role in the regulation of fluid and electrolyte balance and systemic blood pressure. Lack of any of the five dopamine receptor subtypes (D1R, D2R, D3R, D4R, and D5R) results in hypertension. D1R, D2R, and D5R have been reported to be important in the maintenance of a normal redox balance. In the kidney, the antioxidant effects of these receptors are caused by direct and indirect inhibition of pro-oxidant enzymes, specifically, nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase, and stimulation of anti-oxidant enzymes, which can also indirectly inhibit NADPH oxidase activity. Thus, stimulation of the D2R increases the expression of endogenous anti-oxidants, such as Parkinson protein 7 (PARK7 or DJ-1), paraoxonase 2 (PON2), and heme oxygenase 2 (HO-2), all of which can inhibit NADPH oxidase activity. The D5R decreases NADPH oxidase activity, via the inhibition of phospholipase D2, and increases the expression of HO-1, another antioxidant. D1R inhibits NADPH oxidase activity via protein kinase A and protein kinase C cross-talk. In this review, we provide an overview of the protective roles of a specific dopamine receptor subtype on renal oxidative stress, the different mechanisms involved in this effect, and the role of oxidative stress and impairment of dopamine receptor function in the hypertension that arises from the genetic ablation of a specific dopamine receptor gene in mice.
Kidney International, 2014
Determining the individual roles of the two dopamine D 1-like receptors (D 1 R and D 5 R) on sodi... more Determining the individual roles of the two dopamine D 1-like receptors (D 1 R and D 5 R) on sodium transport in the human renal proximal tubule has been complicated by their structural and functional similarity. Here we used a novel D 5 R-selective antagonist (LE-PM436) and D 1 R or D 5 R-specific gene silencing to determine second messenger coupling pathways and heterologous receptor interaction between the two receptors. D 1 R and D 5 R co-localized in renal proximal tubule cells and physically interact, as determined by co-immunoprecipitation and FRET microscopy. Stimulation of renal proximal tubule cells with fenoldopam (D 1 R/D 5 R agonist) led to both adenylyl cyclase and phospholipase C (PLC) activation using real-time FRET biosensors ICUE3 and CYPHR, respectively. Fenoldopam increased cAMP accumulation and PLC activity and inhibited both NHE3 and NaKATPase activities. LE-PM436 and D 5 R siRNA blocked the fenoldopam-stimulated PLC pathway but not cAMP accumulation, while D 1 R siRNA blocked both fenoldopam-stimulated cAMP accumulation and PLC signaling. Either D 1 R or D 5 R siRNA, or LE-PM436 blocked the fenoldopam dependent inhibition of sodium transport. Further studies using the cAMP-selective D 1 R/D 5 R agonist SKF83822 and PLC-selective D 1 R/D 5 R agonist SKF83959 confirmed the cooperative influence of the two pathways on sodium transport. Thus, D 1 R and D 5 R interact in the inhibition of NHE3 and NaKATPase activity, the D 1 R primarily by cAMP, while the D 1 R/D 5 R heteromer modulates the D 1 R effect through a PLC pathway. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Journal of Clinical Investigation, 1996
Since dopamine produced by the kidney is an intrarenal regulator of sodium transport, an abnormal... more Since dopamine produced by the kidney is an intrarenal regulator of sodium transport, an abnormality of the dopaminergic system may be important in the pathogenesis of hypertension. In the spontaneously hypertensive rat (SHR), in spite of normal renal production of dopamine and receptor density, there is defective transduction of the D 1 receptor signal in renal proximal tubules, resulting in decreased inhibition of sodium transport (Na ϩ /H ϩ exchanger [NHE] and Na ϩ /K ϩ ATPase activity) by dopamine. To determine if impaired D 1 receptor regulation of NHE in proximal tubules is related to hypertension, studies were performed in a F2 generation from female Wistar Kyoto (WKY) and male SHR crosses. A D 1 agonist, SKF 81297, inhibited (37.6 Ϯ 4.7%) NHE activity in brush border membranes of normotensive F2s (systolic blood pressure Ͻ 140 mm Hg, n ϭ 7) but not in hypertensive F2s (n ϭ 21). Furthermore, a D 1 agonist, SKF 38393, when infused into the renal artery, dose dependently increased sodium excretion in normotensive F2s (n ϭ 3) without altering renal blood flow but was inactive in hypertensive F2s (n ϭ 21). Since the major D 1 receptor gene expressed in renal proximal tubules is the D 1A subtype, we determined the importance of this gene in the control of blood pressure in mice lacking functional D 1A receptors. Systolic blood pressure was greater in homozygous (n ϭ 6) and heterozygous (n ϭ 5) mice compared to normal sex matched litter mate controls (n ϭ 12); moreover, the mice lacking one or both D 1A alleles developed diastolic hypertension. The cosegregation with hypertension of an impaired D 1 receptor regulation of renal sodium transport and the development of elevated systolic and diastolic pressure in mice lacking one or both D 1A alleles suggest a causal relationship of the D 1A receptor gene with hypertension. (J.
Journal of Biological Chemistry, 2009
During conditions of moderate sodium excess, the dopaminergic system regulates blood pressure and... more During conditions of moderate sodium excess, the dopaminergic system regulates blood pressure and water and electrolyte balance by engendering natriuresis. Dopamine exerts its effects on dopamine receptors, including the dopamine D 3 receptor. G protein-coupled receptor kinase 4 (GRK4), whose gene locus (4p16.3) is linked to essential hypertension, desensitizes the D 1 receptor, another dopamine receptor. This study evaluated the role of GRK4 on D 3 receptor function in human proximal tubule cells. D 3 receptor co-segregated in lipid rafts and co-immunoprecipitated and co-localized in human proximal tubule cells and in proximal and distal tubules and glomeruli of kidneys of Wistar Kyoto rats. Bimolecular fluorescence complementation and confocal microscopy revealed that agonist activation of the receptor initiated the interaction between D 3 receptor and GRK4 at the cell membrane and promoted it intracellularly, presumably en route to endosomal trafficking. Of the four GRK4 splice variants, GRK4-␥ and GRK4-␣ mediated a 3-and 2-fold increase in the phosphorylation of agonist-activated D 3 receptor, respectively. Inhibition of GRK activity with heparin or knockdown of GRK4 expression via RNA interference completely abolished p44/42 phosphorylation and mitogenesis induced by D 3 receptor stimulation. These data demonstrate that GRK4, specifically the GRK4-␥ and GRK4-␣ isoforms, phosphorylates the D 3 receptor and is crucial for its signaling in human proximal tubule cells. During conditions of moderate sodium excess, the dopaminergic system sits at the fulcrum of homeostatic control of water and electrolyte balance and blood pressure (1, 2). Dopamine promotes natriuresis by inhibiting sodium chloride reabsorption in specific segments of the nephron. Dopamine exerts its action on dopamine receptors, which belong to the family of G protein-coupled receptors (GPCRs). 2 The dopamine receptors are classified into two subtypes based on their ability to increase cAMP levels, sequence similarity, G protein coupling, and pharmacological profiles (3, 4). The D 1-like dopamine receptors activate adenylyl cyclase by coupling to stimulatory G␣ s / G␣ olf and include the D 1 (D 1 R) and D 5 receptors (D 5 R). The D 2-like dopamine receptors inhibit adenylyl cyclase by coupling to G␣ i /G␣ o and consist of the D 2 (D 2 R), D 3 (D 3 R), and D 4 (D 4 R) receptors. The D 3 R has also been shown to couple to G␣ o , G␥, and to the stimulatory G␣ s (5, 6). The signal transduction that follows ligand occupation of a GPCR is tightly regulated to limit the specificity and extent of cellular response. GPCR-mediated signal transduction is rapidly dampened via receptor desensitization or the waning of the responsiveness of the receptor to agonist with time. Desensitization involves receptor phosphorylation and is carried out by either GPCR kinases (GRKs) or second messenger-activated kinases such as protein kinase A and protein kinase C. Homologous desensitization involves GRKs that selectively phosphorylate only agonist-activated receptors, whereas heterologous desensitization is carried out by second messenger-dependent kinases that indiscriminately phosphorylate agonist-activated receptors and those that have not been exposed to the agonist (7). The GRKs are serine/threonine protein kinases comprising seven isoforms that are grouped into three subfamilies. GRK1 and GRK7 belong to the rhodopsin kinase subfamily and are expressed exclusively in the retina (8-10). GRK2 and GRK3 phosphorylate the -adrenergic receptor and belong to the -adrenergic receptor kinase subfamily (11), and GRK4, GRK5, and GRK6 belong to the GRK4 subfamily. GRK4 is highly enriched in the testis and, to a lesser degree, in the kidneys (12, 13). Four splice variants of human GRK4 result from the alternative splicing of exons 2 and 15 (11). GRK4-␣ is considered the full-length version, whereas GRK4-,-␥, and-␦ are shortened versions of GRK4-␣ (14). The coding region of the GRK4 gene, whose 4p16.3 locus has been linked to essential hypertension (15, 16), contains several single nucleotide polymorphisms, including R65L, A142V, and A486V, which have been linked to
Journal of Biological Chemistry, 2012
Background: SNX1 is a protein involved in the trafficking of internalized receptors. Results: Inh... more Background: SNX1 is a protein involved in the trafficking of internalized receptors. Results: Inhibition of SNX1 expression leads to failure of D 5 R endocytosis and signaling. Conclusion: Depletion SNX1 function results in D 5 R dysfunction and high blood pressure. Significance: Loss of SNX1 expression may be a novel mechanism for the development of hypertension.
Hypertension Research, 1995
Dopamine is an endogenous catecholamine which exerts its actions by occupancy of specific recepto... more Dopamine is an endogenous catecholamine which exerts its actions by occupancy of specific receptors. Dopamine receptors are classified into two main groups: the two cloned D1-like receptors (D1A and D1B in rats; D1B is also known as Ds in humans) are linked to stimulation of adenylyl cyclase, while the three cloned D2-like receptors (D2 or D2A, D3 or D2B, D4 or D2C) are linked to inhibition of adenylyl cyclase. All these dopamine receptors originally cloned from the brain are expressed in tissues outside the central nervous system including the kidney. Dopamine regulates many cellular activities, including transmembrane ion transport. Activation of D1-like receptor decreases sodium transport by CAMP dependent and cAMP independent mechanisms. Dopamine, via D1-like receptors, may inhibit Na+/H+ exchange activity in renal brush border membranes by a CAMP independent/GS«-linked mechanism. Another CAMP independent pathway of sodium transport inhibition is mediated by phospholipase C, which has several isoforms (PLCI9, PLCy, and PLC o with several members in each). Catecholamines stimulate expression and activity of phospholipase C isoforms in a concentration, time, and receptor-dependent as well as regional and subcellular compartmental-specific manner. In renal cortical membranes, intrarenal administration of norepinephrine for 3-4 h increases PLCI9 expression and activity but has no effect on PLCy activity. In contrast, intrarenal administration of a D1 agonist for 3-4 h increases PLC/91 but decreases PLCy expression and activity. In membranes from LTK-cells transfected with the rat D1A receptor cDNA, D1 receptor stimulation initially increases and then in 4 h decreases PLCy expression and activity, similar to the results found in renal cortical membranes. The initial increase of PLCy expression and activity due to D1 receptors is mediated by protein kinase A.
Hypertension, 2012
Little is known regarding how the kidney shifts from a sodium and water reclaiming state (antinat... more Little is known regarding how the kidney shifts from a sodium and water reclaiming state (antinatriuresis) to a state where sodium and water are eliminated (natriuresis). In human renal proximal tubule cells, sodium reabsorption is decreased by the dopamine D 1 -like receptors (D 1 R/D 5 R) and the angiotensin type 2 receptor (AT 2 R), whereas the angiotensin type 1 receptor increases sodium reabsorption. Aberrant control of these opposing systems is thought to lead to sodium retention and, subsequently, hypertension. We show that D 1 R/D 5 R stimulation increased plasma membrane AT 2 R 4-fold via a D 1 R-mediated, cAMP-coupled, and protein phosphatase 2A–dependent specific signaling pathway. D 1 R/D 5 R stimulation also reduced the ability of angiotensin II to stimulate phospho-extracellular signal–regulated kinase, an effect that was partially reversed by an AT 2 R antagonist. Fenoldopam did not increase AT 2 R recruitment in renal proximal tubule cells with D 1 Rs uncoupled from ...
Hypertension, 2004
Dopamine is an important modulator of blood pressure, in part, by regulating vascular resistance.... more Dopamine is an important modulator of blood pressure, in part, by regulating vascular resistance. To test the hypothesis that D 1 and D 3 receptors interact in vascular smooth muscle cells, we studied A10 cells, a rat aortic smooth muscle cell line, and rat mesenteric arteries that express both dopamine receptor subtypes. Fenoldopam, a D 1 -like receptor agonist, increased both D 1 and D 3 receptor protein in a time-dependent and a concentration-dependent manner in A10 cells. The effect of fenoldopam was specific because a D 1 -like receptor antagonist, SCH23390 (10 −7 M/24 h), completely blocked the stimulatory effect of fenoldopam (10 −7 M/24 h) (D 3 receptor: control=21±1 density units [DU]); SCH23390=23±2 DU; fenoldopam=33±2 DU; fenoldopam+SCH23390=23±2 DU; n=10). D 1 and D 3 receptors physically interacted with each other because fenoldopam (10 −7 M/24 h) increased D 1 /D 3 receptor coimmunoprecipitation (35±5 versus 65±5 DU; n=8). A D 3 receptor agonist, PD128907, relaxed mese...
International Journal of Molecular Sciences, Aug 27, 2013
Dopamine, which is synthesized in the kidney, independent of renal nerves, plays an important rol... more Dopamine, which is synthesized in the kidney, independent of renal nerves, plays an important role in the regulation of fluid and electrolyte balance and systemic blood pressure. Lack of any of the five dopamine receptor subtypes (D1R, D2R, D3R, D4R, and D5R) results in hypertension. D1R, D2R, and D5R have been reported to be important in the maintenance of a normal redox balance. In the kidney, the antioxidant effects of these receptors are caused by direct and indirect inhibition of pro-oxidant enzymes, specifically, nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase, and stimulation of anti-oxidant enzymes, which can also indirectly inhibit NADPH oxidase activity. Thus, stimulation of the D2R increases the expression of endogenous anti-oxidants, such as Parkinson protein 7 (PARK7 or DJ-1), paraoxonase 2 (PON2), and heme oxygenase 2 (HO-2), all of which can inhibit NADPH oxidase activity. The D5R decreases NADPH oxidase activity, via the inhibition of phospholipase D2, and increases the expression of HO-1, another antioxidant. D1R inhibits NADPH oxidase activity via protein kinase A and protein kinase C cross-talk. In this review, we provide an overview of the protective roles of a specific dopamine receptor subtype on renal oxidative stress, the different mechanisms involved in this effect, and the role of oxidative stress and impairment of dopamine receptor function in the hypertension that arises from the genetic ablation of a specific dopamine receptor gene in mice.
International Journal of Molecular Sciences, 2020
The renal dopaminergic system has been identified as a modulator of sodium balance and blood pres... more The renal dopaminergic system has been identified as a modulator of sodium balance and blood pressure. According to the Centers for Disease Control and Prevention, in 2018 in the United States, almost half a million deaths included hypertension as a primary or contributing cause. Renal dopamine receptors, members of the G protein-coupled receptor family, are divided in two groups: D1-like receptors that act to keep the blood pressure in the normal range, and D2-like receptors with a variable effect on blood pressure, depending on volume status. The renal dopamine receptor function is regulated, in part, by its expression in microdomains in the plasma membrane. Lipid rafts form platforms within the plasma membrane for the organization and dynamic contact of molecules involved in numerous cellular processes such as ligand binding, membrane sorting, effector specificity, and signal transduction. Understanding all the components of lipid rafts, their interaction with renal dopamine rece...
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 1998
In vitro studies have suggested that dopamine D1- and D2-like receptors interact to inhibit renal... more In vitro studies have suggested that dopamine D1- and D2-like receptors interact to inhibit renal sodium transport. We used Z-1046, a dopamine receptor agonist with the rank-order potency D3≥ D4> D2> D5> D1, to test the hypothesis that D1- and D2-like receptors interact to inhibit renal sodium transport in vivo in anesthetized rats. Increasing doses of Z-1046, administered via the right renal artery, increased renal blood flow (RBF), urine flow, and absolute and fractional sodium excretion without affecting glomerular filtration rate. For determination of the dopamine receptor involved in the renal functional effects of Z-1046, another group of rats received Z-1046 at 2 μg ⋅ kg−1⋅ min−1( n = 10) in the presence or absence of the D2-like receptor antagonist domperidone and/or the D1-like antagonist SCH-23390. Domperidone alone had no effect but blocked the Z-1046-mediated increase in urine flow and sodium excretion; it enhanced the increase in RBF after Z-1046. SCH-23390 by ...
Hypertension (Dallas, Tex. : 1979), 2018
coding RNA (ncRNA)-mediated targeting of various genes [9] , e.g., G-protein-coupled receptor kin... more coding RNA (ncRNA)-mediated targeting of various genes [9] , e.g., G-protein-coupled receptor kinase type 4 phosphorylates histone deacetylase type 1, promoting its nuclear export to the cytoplasm, resulting in increased Angiotensin II receptor type 1 (AGTR1) expression and greater pressor response to angiotensin II [10]. This review aims to provide an overview of the likely role of ncRNAs in the development of hypertension, as well as advances in ncRNA-based diagnoses and therapeutic approaches. A better understanding of the ncRNA-based molecular mechanisms of the pathogenesis of hypertension is important for the prevention and treatment of hypertension and its complications. 2. ncRNAs Historically, protein-coding genes, with proteins as the final gene products, have been viewed to mediate the phenotype and biological function of any given cell. However, more and more recent studies have shown that ncRNAs participate in the regulation of the expression of protein-coding genes and therefore, play essential roles in many biological processes. These findings have uncovered that ncRNAs orchestrate a hidden layer of generegulation network [11]. These ncRNAs have emerged as dynamic managers that influence the interaction between DNA and the environment that characterizes epigenetics. Generally, ncRNAs are generated in the nucleus, transcribed by RNA polymerase II (RNA Pol II), giving rise to a long precursor mRNA (pre-mRNA), and the main processing mechanism for pre-mRNA transcript is processed by the spliceosome. Apart from the similarities, there are many differences between different types of ncRNAs in biogenesis and processing, which has been recently reviewed elsewhere [12]. Based on size, ncRNAs are classified by the size as the small (~20 nucleotides), intermediate (~20-200 nucleotides), or long (>200 nucleotides). Small ncRNAs (~20 nucleotides) include piwi-interacting RNAs, the largest class of ncRNAs, small interfering RNAs (siRNAs), guide RNA, and miRNAs [13]. Intermediate ncRNAs (~20-200 nucleotides) are involved in splicing during protein synthesis and include nucleolar RNAs that modify ribosome RNA, transcription start site (TSS)-associated RNAs and promoter-associated small RNAs [13]. The rest of the ncRNAs, that are greater than 200 nucleotides, have been grouped into long non-coding RNAs (lncRNAs). Unlike miRNA, lncRNAs have numerous functions in cis and in trans by regulating gene expression with transcription and translation, splicing, chromatin imprinting, and cell cycle development. lncRNAs can silence multiple genes through their interaction with chromatin, or even recruit transcriptional factors to target promoters and induce transcription, indicating that they are central to the epigenetic control of gene expression. The 3'-and 5'-ends of linear RNA transcripts can join and form a loop to make circular RNA (circRNA), a newly identified group of ncRNA, which exhibits stability and high conservation and plays a role in many biological processes [14]. The pathogenesis of hypertension entails a complex interaction of different organs and systems, including an over-activation (e.g., renin-angiotensin-aldosterone system [RAAS], central nervous system, sympathetic nervous systems, central nervous and peripheral nervous system, including renal nerves) or under-activation (e.g., parasympathetic nervous Wu et al.
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology, Jan 21, 2018
Adverse environment in utero can modulate adult phenotypes including blood pressure. Fine particu... more 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 PM2.5-induced hypertension in the offspring. Pregnant Sprague-Dawley rats were given an oropharyngeal drip of PM2.5 (1.0 mg/kg) at gestation day 8, 10, and 12. The blood pressure, 24-hour sodium excretion, and urine volume were measured in the offspring. The expression levels of GRK4 and D1R were determined by immunoblotting. The phosphorylation of D1R was investigated using immunoprecipitation. Plasma malondialdehyde and superoxide dismutase levels were also measured in the offspring. As compared with saline-treated ...
Journal of the American Heart Association, Jan 7, 2018
Epidemiological evidence supports an important association between air pollution exposure and hyp... more Epidemiological evidence supports an important association between air pollution exposure and hypertension. However, the mechanisms are not clear. Our present study found that long-term exposure to fine particulate matter (PM2.5) causes hypertension and impairs renal sodium excretion, which might be ascribed to lower D1 receptor expression and higher D1 receptor phosphorylation, accompanied with a higher G-protein-coupled receptor kinase type 4 (GRK4) expression. The in vivo results were confirmed in in vitro studies (ie, PM2.5 increased basal and decreased D1 receptor mediated inhibitory effect on Na+-K+ ATPase activity, decreased D1 receptor expression, and increased D1 receptor phosphorylation in renal proximal tubule cells). The downregulation of D1 receptor expression and function might be attributable to a higher GRK4 expression after the exposure of renal proximal tubule cells to PM2.5, because downregulation of GRK4 by small-interfering RNA reversed the D1 receptor expressio...
American Journal of Hypertension, 2003
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 ...
American Journal of Hypertension, 2005
Basal cAMP level (pmol/mg protein) was lower in SHR than in WKY (5.5Ϯ0.1 vs. 8.4Ϯ0.4, pϽ0.01, nϭ3... more Basal cAMP level (pmol/mg protein) was lower in SHR than in WKY (5.5Ϯ0.1 vs. 8.4Ϯ0.4, pϽ0.01, nϭ3) rats. Although terbutaline (10-8 M, 20 min) increased cAMP accumulation to a similar degree in WKY and SHRs (63Ϯ10% vs. 68Ϯ8%, pϾ0.05, nϭ3), it inhibited NHE3 activity to a greater extent in WKY (41Ϯ15 %) than in SHRs (32Ϯ13 %) (pϽ0.05, nϭ12). Conclusion: The lower amount of 2-AR on the cell surface of SHR IRPTCs in comparison to WKY may explain the decreased ability of 2-AR to inhibit NHE3 activity in SHRs. The inhibition of NHE3 activity by 2-AR is apparently independent of cAMP.
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...
American Journal of Hypertension, 2005
Basal cAMP level (pmol/mg protein) was lower in SHR than in WKY (5.5Ϯ0.1 vs. 8.4Ϯ0.4, pϽ0.01, nϭ3... more Basal cAMP level (pmol/mg protein) was lower in SHR than in WKY (5.5Ϯ0.1 vs. 8.4Ϯ0.4, pϽ0.01, nϭ3) rats. Although terbutaline (10-8 M, 20 min) increased cAMP accumulation to a similar degree in WKY and SHRs (63Ϯ10% vs. 68Ϯ8%, pϾ0.05, nϭ3), it inhibited NHE3 activity to a greater extent in WKY (41Ϯ15 %) than in SHRs (32Ϯ13 %) (pϽ0.05, nϭ12). Conclusion: The lower amount of 2-AR on the cell surface of SHR IRPTCs in comparison to WKY may explain the decreased ability of 2-AR to inhibit NHE3 activity in SHRs. The inhibition of NHE3 activity by 2-AR is apparently independent of cAMP.
American journal of physiology. Renal physiology, 2014
The homeostatic control of blood pressure hinges upon the delicate balance between prohypertensin... more The homeostatic control of blood pressure hinges upon the delicate balance between prohypertensinogenic and antihypertensinogenic systems. D₁-like dopamine receptors [dopamine D₁ and D₅ receptors (D₁Rs and D₅Rs, respectively)] and the α₁A-adrenergic receptor (α₁A-AR) are expressed in the renal proximal tubule and engender opposing effects on Na(+) transport, i.e., natriuresis (via D₁Rs and D5Rs) or antinatriuresis (via α₁A-ARs). We tested the hypothesis that the D₁R/D₅R regulates the α₁A-AR. D₁-like dopamine receptors coimmunoprecipitated, colocalized, and cofractionated with α₁A-ARs in lipid rafts in immortalized human renal proximal tubule cells. Long-term treatment with the D₁R/D₅R agonist fenoldopam resulted in decreased D₁R and D₅R expression but increased α₁A-AR abundance in the plasma membrane. Short-term fenoldopam treatment stimulated the translocation of Na(+)-K(+)-ATPase from the plasma membrane to the cytosol that was partially reversed by an α₁A-AR agonist, which by its...
International Journal of Molecular Sciences, 2013
Dopamine, which is synthesized in the kidney, independent of renal nerves, plays an important rol... more Dopamine, which is synthesized in the kidney, independent of renal nerves, plays an important role in the regulation of fluid and electrolyte balance and systemic blood pressure. Lack of any of the five dopamine receptor subtypes (D1R, D2R, D3R, D4R, and D5R) results in hypertension. D1R, D2R, and D5R have been reported to be important in the maintenance of a normal redox balance. In the kidney, the antioxidant effects of these receptors are caused by direct and indirect inhibition of pro-oxidant enzymes, specifically, nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase, and stimulation of anti-oxidant enzymes, which can also indirectly inhibit NADPH oxidase activity. Thus, stimulation of the D2R increases the expression of endogenous anti-oxidants, such as Parkinson protein 7 (PARK7 or DJ-1), paraoxonase 2 (PON2), and heme oxygenase 2 (HO-2), all of which can inhibit NADPH oxidase activity. The D5R decreases NADPH oxidase activity, via the inhibition of phospholipase D2, and increases the expression of HO-1, another antioxidant. D1R inhibits NADPH oxidase activity via protein kinase A and protein kinase C cross-talk. In this review, we provide an overview of the protective roles of a specific dopamine receptor subtype on renal oxidative stress, the different mechanisms involved in this effect, and the role of oxidative stress and impairment of dopamine receptor function in the hypertension that arises from the genetic ablation of a specific dopamine receptor gene in mice.
Kidney International, 2014
Determining the individual roles of the two dopamine D 1-like receptors (D 1 R and D 5 R) on sodi... more Determining the individual roles of the two dopamine D 1-like receptors (D 1 R and D 5 R) on sodium transport in the human renal proximal tubule has been complicated by their structural and functional similarity. Here we used a novel D 5 R-selective antagonist (LE-PM436) and D 1 R or D 5 R-specific gene silencing to determine second messenger coupling pathways and heterologous receptor interaction between the two receptors. D 1 R and D 5 R co-localized in renal proximal tubule cells and physically interact, as determined by co-immunoprecipitation and FRET microscopy. Stimulation of renal proximal tubule cells with fenoldopam (D 1 R/D 5 R agonist) led to both adenylyl cyclase and phospholipase C (PLC) activation using real-time FRET biosensors ICUE3 and CYPHR, respectively. Fenoldopam increased cAMP accumulation and PLC activity and inhibited both NHE3 and NaKATPase activities. LE-PM436 and D 5 R siRNA blocked the fenoldopam-stimulated PLC pathway but not cAMP accumulation, while D 1 R siRNA blocked both fenoldopam-stimulated cAMP accumulation and PLC signaling. Either D 1 R or D 5 R siRNA, or LE-PM436 blocked the fenoldopam dependent inhibition of sodium transport. Further studies using the cAMP-selective D 1 R/D 5 R agonist SKF83822 and PLC-selective D 1 R/D 5 R agonist SKF83959 confirmed the cooperative influence of the two pathways on sodium transport. Thus, D 1 R and D 5 R interact in the inhibition of NHE3 and NaKATPase activity, the D 1 R primarily by cAMP, while the D 1 R/D 5 R heteromer modulates the D 1 R effect through a PLC pathway. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Journal of Clinical Investigation, 1996
Since dopamine produced by the kidney is an intrarenal regulator of sodium transport, an abnormal... more Since dopamine produced by the kidney is an intrarenal regulator of sodium transport, an abnormality of the dopaminergic system may be important in the pathogenesis of hypertension. In the spontaneously hypertensive rat (SHR), in spite of normal renal production of dopamine and receptor density, there is defective transduction of the D 1 receptor signal in renal proximal tubules, resulting in decreased inhibition of sodium transport (Na ϩ /H ϩ exchanger [NHE] and Na ϩ /K ϩ ATPase activity) by dopamine. To determine if impaired D 1 receptor regulation of NHE in proximal tubules is related to hypertension, studies were performed in a F2 generation from female Wistar Kyoto (WKY) and male SHR crosses. A D 1 agonist, SKF 81297, inhibited (37.6 Ϯ 4.7%) NHE activity in brush border membranes of normotensive F2s (systolic blood pressure Ͻ 140 mm Hg, n ϭ 7) but not in hypertensive F2s (n ϭ 21). Furthermore, a D 1 agonist, SKF 38393, when infused into the renal artery, dose dependently increased sodium excretion in normotensive F2s (n ϭ 3) without altering renal blood flow but was inactive in hypertensive F2s (n ϭ 21). Since the major D 1 receptor gene expressed in renal proximal tubules is the D 1A subtype, we determined the importance of this gene in the control of blood pressure in mice lacking functional D 1A receptors. Systolic blood pressure was greater in homozygous (n ϭ 6) and heterozygous (n ϭ 5) mice compared to normal sex matched litter mate controls (n ϭ 12); moreover, the mice lacking one or both D 1A alleles developed diastolic hypertension. The cosegregation with hypertension of an impaired D 1 receptor regulation of renal sodium transport and the development of elevated systolic and diastolic pressure in mice lacking one or both D 1A alleles suggest a causal relationship of the D 1A receptor gene with hypertension. (J.
Journal of Biological Chemistry, 2009
During conditions of moderate sodium excess, the dopaminergic system regulates blood pressure and... more During conditions of moderate sodium excess, the dopaminergic system regulates blood pressure and water and electrolyte balance by engendering natriuresis. Dopamine exerts its effects on dopamine receptors, including the dopamine D 3 receptor. G protein-coupled receptor kinase 4 (GRK4), whose gene locus (4p16.3) is linked to essential hypertension, desensitizes the D 1 receptor, another dopamine receptor. This study evaluated the role of GRK4 on D 3 receptor function in human proximal tubule cells. D 3 receptor co-segregated in lipid rafts and co-immunoprecipitated and co-localized in human proximal tubule cells and in proximal and distal tubules and glomeruli of kidneys of Wistar Kyoto rats. Bimolecular fluorescence complementation and confocal microscopy revealed that agonist activation of the receptor initiated the interaction between D 3 receptor and GRK4 at the cell membrane and promoted it intracellularly, presumably en route to endosomal trafficking. Of the four GRK4 splice variants, GRK4-␥ and GRK4-␣ mediated a 3-and 2-fold increase in the phosphorylation of agonist-activated D 3 receptor, respectively. Inhibition of GRK activity with heparin or knockdown of GRK4 expression via RNA interference completely abolished p44/42 phosphorylation and mitogenesis induced by D 3 receptor stimulation. These data demonstrate that GRK4, specifically the GRK4-␥ and GRK4-␣ isoforms, phosphorylates the D 3 receptor and is crucial for its signaling in human proximal tubule cells. During conditions of moderate sodium excess, the dopaminergic system sits at the fulcrum of homeostatic control of water and electrolyte balance and blood pressure (1, 2). Dopamine promotes natriuresis by inhibiting sodium chloride reabsorption in specific segments of the nephron. Dopamine exerts its action on dopamine receptors, which belong to the family of G protein-coupled receptors (GPCRs). 2 The dopamine receptors are classified into two subtypes based on their ability to increase cAMP levels, sequence similarity, G protein coupling, and pharmacological profiles (3, 4). The D 1-like dopamine receptors activate adenylyl cyclase by coupling to stimulatory G␣ s / G␣ olf and include the D 1 (D 1 R) and D 5 receptors (D 5 R). The D 2-like dopamine receptors inhibit adenylyl cyclase by coupling to G␣ i /G␣ o and consist of the D 2 (D 2 R), D 3 (D 3 R), and D 4 (D 4 R) receptors. The D 3 R has also been shown to couple to G␣ o , G␥, and to the stimulatory G␣ s (5, 6). The signal transduction that follows ligand occupation of a GPCR is tightly regulated to limit the specificity and extent of cellular response. GPCR-mediated signal transduction is rapidly dampened via receptor desensitization or the waning of the responsiveness of the receptor to agonist with time. Desensitization involves receptor phosphorylation and is carried out by either GPCR kinases (GRKs) or second messenger-activated kinases such as protein kinase A and protein kinase C. Homologous desensitization involves GRKs that selectively phosphorylate only agonist-activated receptors, whereas heterologous desensitization is carried out by second messenger-dependent kinases that indiscriminately phosphorylate agonist-activated receptors and those that have not been exposed to the agonist (7). The GRKs are serine/threonine protein kinases comprising seven isoforms that are grouped into three subfamilies. GRK1 and GRK7 belong to the rhodopsin kinase subfamily and are expressed exclusively in the retina (8-10). GRK2 and GRK3 phosphorylate the -adrenergic receptor and belong to the -adrenergic receptor kinase subfamily (11), and GRK4, GRK5, and GRK6 belong to the GRK4 subfamily. GRK4 is highly enriched in the testis and, to a lesser degree, in the kidneys (12, 13). Four splice variants of human GRK4 result from the alternative splicing of exons 2 and 15 (11). GRK4-␣ is considered the full-length version, whereas GRK4-,-␥, and-␦ are shortened versions of GRK4-␣ (14). The coding region of the GRK4 gene, whose 4p16.3 locus has been linked to essential hypertension (15, 16), contains several single nucleotide polymorphisms, including R65L, A142V, and A486V, which have been linked to
Journal of Biological Chemistry, 2012
Background: SNX1 is a protein involved in the trafficking of internalized receptors. Results: Inh... more Background: SNX1 is a protein involved in the trafficking of internalized receptors. Results: Inhibition of SNX1 expression leads to failure of D 5 R endocytosis and signaling. Conclusion: Depletion SNX1 function results in D 5 R dysfunction and high blood pressure. Significance: Loss of SNX1 expression may be a novel mechanism for the development of hypertension.
Hypertension Research, 1995
Dopamine is an endogenous catecholamine which exerts its actions by occupancy of specific recepto... more Dopamine is an endogenous catecholamine which exerts its actions by occupancy of specific receptors. Dopamine receptors are classified into two main groups: the two cloned D1-like receptors (D1A and D1B in rats; D1B is also known as Ds in humans) are linked to stimulation of adenylyl cyclase, while the three cloned D2-like receptors (D2 or D2A, D3 or D2B, D4 or D2C) are linked to inhibition of adenylyl cyclase. All these dopamine receptors originally cloned from the brain are expressed in tissues outside the central nervous system including the kidney. Dopamine regulates many cellular activities, including transmembrane ion transport. Activation of D1-like receptor decreases sodium transport by CAMP dependent and cAMP independent mechanisms. Dopamine, via D1-like receptors, may inhibit Na+/H+ exchange activity in renal brush border membranes by a CAMP independent/GS«-linked mechanism. Another CAMP independent pathway of sodium transport inhibition is mediated by phospholipase C, which has several isoforms (PLCI9, PLCy, and PLC o with several members in each). Catecholamines stimulate expression and activity of phospholipase C isoforms in a concentration, time, and receptor-dependent as well as regional and subcellular compartmental-specific manner. In renal cortical membranes, intrarenal administration of norepinephrine for 3-4 h increases PLCI9 expression and activity but has no effect on PLCy activity. In contrast, intrarenal administration of a D1 agonist for 3-4 h increases PLC/91 but decreases PLCy expression and activity. In membranes from LTK-cells transfected with the rat D1A receptor cDNA, D1 receptor stimulation initially increases and then in 4 h decreases PLCy expression and activity, similar to the results found in renal cortical membranes. The initial increase of PLCy expression and activity due to D1 receptors is mediated by protein kinase A.
Hypertension, 2012
Little is known regarding how the kidney shifts from a sodium and water reclaiming state (antinat... more Little is known regarding how the kidney shifts from a sodium and water reclaiming state (antinatriuresis) to a state where sodium and water are eliminated (natriuresis). In human renal proximal tubule cells, sodium reabsorption is decreased by the dopamine D 1 -like receptors (D 1 R/D 5 R) and the angiotensin type 2 receptor (AT 2 R), whereas the angiotensin type 1 receptor increases sodium reabsorption. Aberrant control of these opposing systems is thought to lead to sodium retention and, subsequently, hypertension. We show that D 1 R/D 5 R stimulation increased plasma membrane AT 2 R 4-fold via a D 1 R-mediated, cAMP-coupled, and protein phosphatase 2A–dependent specific signaling pathway. D 1 R/D 5 R stimulation also reduced the ability of angiotensin II to stimulate phospho-extracellular signal–regulated kinase, an effect that was partially reversed by an AT 2 R antagonist. Fenoldopam did not increase AT 2 R recruitment in renal proximal tubule cells with D 1 Rs uncoupled from ...
Hypertension, 2004
Dopamine is an important modulator of blood pressure, in part, by regulating vascular resistance.... more Dopamine is an important modulator of blood pressure, in part, by regulating vascular resistance. To test the hypothesis that D 1 and D 3 receptors interact in vascular smooth muscle cells, we studied A10 cells, a rat aortic smooth muscle cell line, and rat mesenteric arteries that express both dopamine receptor subtypes. Fenoldopam, a D 1 -like receptor agonist, increased both D 1 and D 3 receptor protein in a time-dependent and a concentration-dependent manner in A10 cells. The effect of fenoldopam was specific because a D 1 -like receptor antagonist, SCH23390 (10 −7 M/24 h), completely blocked the stimulatory effect of fenoldopam (10 −7 M/24 h) (D 3 receptor: control=21±1 density units [DU]); SCH23390=23±2 DU; fenoldopam=33±2 DU; fenoldopam+SCH23390=23±2 DU; n=10). D 1 and D 3 receptors physically interacted with each other because fenoldopam (10 −7 M/24 h) increased D 1 /D 3 receptor coimmunoprecipitation (35±5 versus 65±5 DU; n=8). A D 3 receptor agonist, PD128907, relaxed mese...