Biomedical subjects

Pedro A Jose

Publications and source records attributed to Pedro A Jose.

At least 37 records · Page 2Linked to original sources

PubMed2005

D5 dopamine receptor regulation of phospholipase D.

D(1)-like receptors have been reported to decrease oxidative stress in vascular smooth muscle cells by decreasing phospholipase D (PLD) activity. However, the PLD isoform regulated by D(1)-like receptors (D(1) or D(5)) and whether abnormal regulation of PLD by D(1)-like receptors plays a role in the pathogenesis of hypertension are unknown. The hypothesis that the D(5) receptor is the D(1)-like receptor that inhibits PLD activity and serves to regulate blood pressure was tested using D(5) receptor mutant mice (D(5)(-/-)). We found that in the mouse kidney, PLD2, like the D(5) receptor, is mainly expressed in renal brush-border membranes, whereas PLD1 is mainly expressed in renal vessels with faint staining in brush-border membranes and collecting ducts. Total renal PLD activity is increased in D(5)(-/-) mice relative to congenic D(5) wild-type (D(5)(+/+)) mice. PLD2, but not PLD1, expression is greater in D(5)(-/-) than in D(5)(+/+) mice. The D(5) receptor agonist fenoldopam decreases PLD2, but not PLD1, expression and activity in human embryonic kidney-293 cells heterologously expressing the human D(5) receptor, effects that are blocked by the D(5) receptor antagonist SCH-23390. These studies show that the D(5) receptor regulates PLD2 activity and expression. The hypertension in the D(5)(-/-) mice is associated with increased PLD expression and activity. Impaired D(5) receptor regulation of PLD2 may play a role in the pathogenesis of hypertension.

Animals↗

PubMed2005

Dopamine receptor and hypertension.

Dopamine plays an important role in the pathogenesis of hypertension by regulating epithelial sodium transport and reactive oxygen and by interacting with vasopressin, renin-angiotensin, and the sympathetic nervous system. Decreased renal dopamine production and/or impaired dopamine receptor function have been reported in hypertension. Disruption of any of the dopamine receptors (D(1), D(2), D(3), D(4), and D(5)) results in hypertension. In this paper, we review the mechanisms by which hypertension develops when dopamine receptor function is perturbed.

Animals↗

PubMed2005

[Hypertension in D3 dopamine receptor deficient mice].

OBJECTIVE: To investigate the mechanisms by which hypertension occurs in D(3) dopamine receptor null mice (D(3)-/-). METHODS: Several parameters, including blood pressure, renal sodium excretion, D(3) receptor protein and mRNA expression, plasma renin activity, norepinephrine concentration and AT(1) receptor expression were checked in D(3)-/- mice and their littermate wild type mice (D(3)+/+). Moreover, the vasorelaxant effect of D(3) receptor stimulation was measured with ex-vivo mesenteric artery isolated from Wistar-Kyoto rats. RESULTS: Blood pressure was higher in D(3)-/- mice compared with that in D(3)+/+ mice, salt-loading had no effect on blood pressure in both groups, at the last period, sodium excretion was lower in D(3)-/- mice as compared with D(3)+/+ mice, renal renin activity and AT(1) receptor expression were higher in D(3) -/- [corrected] mice than in D(3) +/+ [corrected] mice. In contrast, no difference of renal norepinephrine was found in two groups. When using angiotensin II subtype-1 receptor antagonist, the systolic blood pressure declined for a longer duration in mutant mice than in wild-type mice. Vaso-relaxation was found in ex-vivo isolated mesenteric artery when D(3) receptor was stimulated. CONCLUSIONS: Elevation of blood pressure in D(3)-/- mice might be related with impaired renal sodium excretion and vaso-relaxation in resistance artery.

Animals↗

PubMed2004

Functional genomics of the dopaminergic system in hypertension.

Abnormalities in dopamine production and receptor function have been described in human essential hypertension and rodent models of genetic hypertension. Under normal conditions, D(1)-like receptors (D(1) and D(5)) inhibit sodium transport in the kidney and intestine. However, in the Dahl salt-sensitive and spontaneously hypertensive rats (SHRs) and in humans with essential hypertension, the D(1)-like receptor-mediated inhibition of epithelial sodium transport is impaired because of an uncoupling of the D(1)-like receptor from its G protein/effector complex. The uncoupling is receptor specific, organ selective, nephron-segment specific, precedes the onset of hypertension, and cosegregates with the hypertensive phenotype. The defective transduction of the renal dopaminergic signal is caused by activating variants of G protein-coupled receptor kinase type 4 (GRK4: R65L, A142V, A486V). The GRK4 locus is linked to and GRK4 gene variants are associated with human essential hypertension, especially in salt-sensitive hypertensive subjects. Indeed, the presence of three or more GRK4 variants impairs the natriuretic response to dopaminergic stimulation in humans. In genetically hypertensive rats, renal inhibition of GRK4 expression ameliorates the hypertension. In mice, overexpression of GRK4 variants causes hypertension either with or without salt sensitivity according to the variant. GRK4 gene variants, by preventing the natriuretic function of the dopaminergic system and by allowing the antinatriuretic factors (e.g., angiotensin II type 1 receptor) to predominate, may be responsible for salt sensitivity. Subclasses of hypertension may occur because of additional perturbations caused by variants of other genes, the quantitative interaction of which may vary depending upon the genetic background.

Animals↗

PubMed2004

Dopamine D3 receptor-mediated inhibition of Na+/H+ exchanger activity in normotensive and spontaneously hypertensive rat proximal tubular epithelial cells.

This study evaluated the response of the Na(+)/H(+) exchanger (NHE) to dopamine D(1)- and D(2)-like receptor stimulation in immortalized renal proximal tubular epithelial cells and freshly isolated renal proximal tubules from the spontaneously hypertensive rat (SHR) and their normotensive controls (Wistar Kyoto rats; WKY). Stimulation of D(1)-like receptors with SKF 38393 attenuated NHE activity in WKY cells (IC(50)=151 nM), but not in SHR cells. Stimulation of D(2)-like receptors with quinerolane (IC(50)=120 nM) attenuated NHE activity in SHR cells, but not in WKY cells. Forskolin was equipotent in SHR and WKY cells in inhibiting NHE activity. The effect of SKF 38393 was abolished by overnight treatment of WKY cells with cholera toxin (CTX, 500 ng ml(-1)), but not with pertussis toxin (PTX, 100 ng ml(-1)). The effect of quinerolane (1 microm) was abolished by overnight treatment of SHR cells with PTX, but not with CTX. The D(3) receptor agonist 7-OH-DPAT (IC(50)=0.8 microM) attenuated NHE activity in SHR cells only. This effect was abolished by S-sulpiride and by overnight treatment with PTX. The D(4) receptor agonist RBI 257 did not affect NHE activity. The 7-OH-DPAT inhibited NHE activity in freshly isolated renal proximal tubules from 4- and 12-week-old SHR and 12-week-old WKY, but not in freshly isolated renal proximal tubules from 4-week-old WKY. It is concluded that D(3) receptors coupled to a G(i/o) protein play a role in the handling of tubular Na(+), namely through inhibition of the NHE activity, this being of particular relevance in the SHR, which fail to respond to D(1)-like dopamine receptor stimulation.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed2004

Gialpha3 protein-coupled dopamine D3 receptor-mediated inhibition of renal NHE3 activity in SHR proximal tubular cells is a PLC-PKC-mediated event.

This study evaluated the transduction pathway associated with type 3 Na(+)/H(+) exchanger (NHE3) activity-induced inhibition during dopamine D(3) receptor activation in immortalized renal proximal tubular epithelial cells from the spontaneously hypertensive rat. The dopamine D(3) receptor agonist 7-OH-DPAT decreased NHE3 activity, which was prevented by the D(2)-like receptor antagonist S-sulpiride, pertussis toxin (PTX; overnight treatment), and the PKC inhibitor chelerythrine, but not by cholera toxin (overnight treatment), the MAPK inhibitor PD-098059, or the p38 inhibitor SB-203580. The PKA inhibitor H-89 abolished the inhibitory effects of forskolin on NHE3 activity, but not that of 7-OH-DPAT. The phospholipase C (PLC) inhibitor U-73122 prevented the inhibitory effects of 7-OH-DPAT, whereas PDBu and 7-OH-DPAT increased PLC activity and reduced NHE3 activity; downregulation of PKC abolished the inhibitory effects of both PDBu and 7-OH-DPAT on NHE activity. The inhibition of NHE3 activity by GTPgammaS and the prevention of the effect of 7-OH-DPAT by PTX suggest an involvement of a G(i/o) protein coupled to the dopamine D(3) receptor. Indeed, the 7-OH-DPAT-induced decrease in NHE3 activity was abolished in cells treated overnight with the anti-G(i)alpha3 antibody, but not in cells treated with antibodies against G(q/11), G(s)alpha, G(beta), and G(i)alpha1,2 proteins. The calcium ionophore A-23187 and the Ca(2+)-ATPase inhibitor thapsigargin increased intracellular Ca(2+) but did not affect NHE3 activity. However, the inhibitory effects of PDBu and 7-OH-DPAT on NHE3 activity were completely abolished by A-23287 and thapsigargin. It is concluded that inhibition of NHE3 activity by dopamine D(3) receptors coupled to G(i)alpha3 proteins is a PLC-PKC-mediated event, modulated by intracellular Ca(2+).

Animals↗

PubMed2004

Involvement of G protein-coupled receptor kinase 4 and 6 in rapid desensitization of dopamine D1 receptor in rat IEC-6 intestinal epithelial cells.

Dopamine-induced inhibition of Na(+)-K(+)-ATPase has been suggested to play a role in the regulation of Na(+) absorption at the intestinal level, and these effects were mediated by dopamine D(1)-like receptors. The aim of this work was to evaluate the effect of the activation of the D(1)-like receptors on the activity of the Na(+)/H(+) exchanger (NHE) in the rat intestinal epithelial cell line IEC-6. The presence of D(1) receptors was confirmed by immunoblotting. The dopamine D(1)-like receptor agonist SKF-38393 produced a concentration-dependent inhibition of NHE activity and stimulation of adenylyl cyclase (AC), this being antagonized by the D(1) selective antagonist SKF-83566. Effects of SKF-38393 on NHE and AC activities were maximal at 5 min of exposure to the agonist and rapidly diminished with no effect at 25 min. Exposure of cells for 25 min to dibutyryl-cAMP (0.5 mM) or to the AC activator forskolin (3 microM) effectively inhibited NHE activity. Pretreatment of cells with heparin (1 microM), a nonselective G protein-coupled receptor kinase (GRK) inhibitor, prevented the loss of effects on NHE activity after 25 min exposure to SKF-38393. The presence of GRK4, GRK6A, and GRK6B was confirmed by immunoblotting. Overnight treatment with the anti-GRK4-6 antibody complexed with Lipofectin was also effective in preventing loss of the effects of SKF-38393 on NHE and AC activities. It is concluded that dopamine D(1) receptors in IEC-6 rapidly desensitize to D(1)-like agonist stimulation and GRK4 and 6 appear to be involved in agonist-mediated responsiveness and desensitization.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed2004

Defective D1-like receptor-mediated inhibition of the Cl-/HCO3- exchanger in immortalized SHR proximal tubular epithelial cells.

The sensitivity of the Cl(-)/HCO(3)(-) exchanger to dopamine D(1)- and D(2)-like receptor stimulation in immortalized renal proximal tubular epithelial cells from the spontaneous hypertensive rat (SHR) and Wistar-Kyoto rat (WKY) was examined. The activity of the Cl(-)/HCO(3)(-) exchanger (in pH U/s) in SHR cells (0.00191) was greater than in WKY cells (0.00126). The activity of Cl(-)/HCO(3)(-) exchanger was exclusively observed at the apical cell side and probably occurs through the SLC26A6 anion transporter that is expressed in both WKY and SHR cells. Stimulation of D(1)-like receptors with SKF-38393 markedly attenuated the HCO(3)(-)-dependent intracellular pH recovery in WKY cells but not in SHR cells. Stimulation of D(2)-like receptors with quinerolane did not alter Cl(-)/HCO(3)(-) exchanger activity in both WKY and SHR cells. The selective D(1)-like receptor antagonist SKF-83566 prevented the effect of SKF-38393. Both WKY and SHR cells responded to dibutyryl-cAMP (DBcAMP) with inhibition of the Cl(-)/HCO(3)(-) exchanger, and downregulation of PKA (overnight exposure to DBcAMP) abolished the inhibitory effect of both DBcAMP and SKF-38393 in WKY cells. Both SHR and WKY cells responded to forskolin with increases in the formation of cAMP. However, only WKY responded to SKF-38393 with increases in the formation of cAMP that was prevented by SKF-83566. It is concluded that WKY cells respond to D(1)-like dopamine receptor stimulation with inhibition of the apical Cl(-)/HCO(3)(-) (SLC26A6) exchanger and SHR cells have a defective D(1)-like dopamine response.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed2004

Dopamine D1 receptor augmentation of D3 receptor action in rat aortic or mesenteric vascular smooth muscles.

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 mesenteric arterial rings independent of the endothelium, effects that were blocked by a D(3) receptor antagonist, U99194A. Costimulation of D(1) and D(3) receptors led to additive vasorelaxation. We conclude that the D(1) receptor regulates the D(3) receptor by physical interaction and receptor expression. D(1) receptor stimulation augments D(3) receptor vasorelaxant effects. An interaction of D(1) and D(3) receptors may be involved in the regulation of blood pressure.

Animals↗

PubMed2004

Aberrant D1 and D3 dopamine receptor transregulation in hypertension.

Dopamine plays a role in the regulation of blood pressure by inhibition of sodium transport in renal proximal tubules (RPTs) and relaxation of vascular smooth muscles. Because dopamine receptors can regulate and interact with each other, we studied the interaction of D(1) and D(3) receptors in immortalized RPT cells and mesenteric arteries from Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHRs), and in human coronary artery smooth muscle cells (CASMCs). In WKY rats, the D(1)-like agonist, fenoldopam, increased D(3) receptor protein in a time-dependent and concentration-dependent manner (EC(50)=4.5x10(-9) M, t(1/2)=15.8 hours). In SHRs, fenoldopam (10(-5) M) actually decreased the expression of D(3) receptors. D(1) and D(3) receptor co-immunoprecipitation was increased by fenoldopam (10(-7) M/24 h) in WKY rats but not in SHRs. The effects of fenoldopam in CASMCs were similar as those in WKY RPT cells (ie, fenoldopam increased D(1) and D(3) receptor proteins). Both D(3) (PD128907, Emax=80%+/-6%, pED(50)=5+/-0.1) and D(1)-like receptor (fenoldopam, Emax=81%+/-8%, pED(50)=5+/-0.2, n=12) agonists relaxed mesenteric arterial rings. Co-stimulation of D(1) and D(3) receptors led to additive vasorelaxation in WKY rats, but not in SHRs. D(1) and D(3) receptors interact differently in WKY and SHRs. Altered interactions between D(1) and D(3) receptors may play a role in the pathogenesis of genetic hypertension, including human hypertension, because these receptors also interact in human vascular smooth muscle cells.

Animals↗

PubMed2004

Neonatal blood pressure regulation.

Hypertension is often viewed solely as a disease of the adult. However, early indicators of hypertension are frequently observed in young children and neonates. Having an adequate appreciation of the normal range of infant blood pressure is critical for the appropriate management of the conditions associated with elevated or abnormally low blood pressure. In healthy neonates, systolic blood pressure increases rapidly during the first 6 weeks of life with the most rapid rise observed during the first 5 days. A similar pattern is observed for diastolic pressures. The observed increases in blood pressure are positively correlated with birth weight and both gestational and postnatal age. The incidence of hypertension in the neonate has been reported to range from 0.2% to 2.6% and is frequently an indicator of other renal or cardiovascular abnormalities. Systemic hypotension is reported in 24% to 45% of very low birth weight infants and is frequently caused by hypovolemia. The regulation of blood pressure is complex and the mechanisms involved remain to be fully elucidated. The results of several investigations into the molecular mechanism(s) of hypertension are considered.

Aging↗

PubMed2004

Protein phosphatase 2A B56alpha during development in the spontaneously hypertensive rat.

Mistargeting of the regulatory subunit of protein phosphatase 2A (PP2A), B56alpha is involved in the hyperphosphorylation and desensitization of the D1 dopamine receptor in renal proximal tubules of spontaneously hypertensive rats (SHRs). However, the renal expression of B56alpha before hypertension develops is not known. Therefore, we studied the expression of B56alpha and PP2A activity in the kidney during development in the SHR and its normotensive control, the Wistar-Kyoto (WKY) rat. PP2A B56alpha was expressed in proximal and distal tubules with no differences in the pattern of expression in WKY and SHRs at any age. In brush border membranes of renal proximal tubules, PP2A B56alpha protein was greatest in the immature rats and decreased with development. However, PP2A activity did not change with age. PP2A B56alpha protein and PP2A activity were similar in WKY and SHRs except at 2 weeks when both PP2A B56alpha protein and PP2A activity were higher in SHRs than in WKY rats. The PP2A catalytic subunit co-immunoprecipitated with the D1 receptor in renal proximal tubule cells. It is possible that the increased expression of PP2A B56alpha and increased basal PP2A activity in the young, especially in the SHRs, may serve as a compensatory mechanism in the increased phosphorylation and decreased renal D1 receptor function, including D1-receptor mediated stimulation in renal proximal tubules of SHRs.

Animals↗

PubMed2004

D5 dopamine receptor knockout mice and hypertension.

Abnormalities in dopamine production and receptor function have been described in human essential hypertension and rodent models of genetic hypertension. All of the five dopamine receptor genes (D1, D2, D3, D4, and D5) expressed in mammals and some of their regulators are in loci linked to hypertension in humans and in rodents. Under normal conditions, D1-like receptors (D1 and D5) inhibit sodium transport in the kidney and the intestine. However, in the Dahl salt-sensitive and spontaneously hypertensive rats, and humans with essential hypertension, the D1-like receptor-mediated inhibition of sodium transport is impaired because of an uncoupling of the D1-like receptor from its G protein/effector complex. The uncoupling is genetic, and receptor-, organ-, and nephron segment-specific. In human essential hypertension, the uncoupling of the D1 receptor from its G protein/effector complex is caused by an agonist-independent serine phosphorylation/desensitization by constitutively active variants of the G protein-coupled receptor kinase type 4. The D5 receptor is also important in blood pressure regulation. Disruption of the D5 or the D1 receptor gene in mice increases blood pressure. However, unlike the D1 receptor, the hypertension in D5 receptor null mice is caused by increased activity of the sympathetic nervous system, apparently due to activation of oxytocin, V1 vasopressin, and non-N-methyl D-aspartate receptors in the central nervous system. The cause of the activation of these receptors remains to be determined.

Animals↗

PubMed2004

Over-expression of renal LAT1 and LAT2 and enhanced L-DOPA uptake in SHR immortalized renal proximal tubular cells.

BACKGROUND: Spontaneously hypertensive rats (SHR) may have an increased renal production of dopamine. LAT2 promotes L-DOPA renal uptake, and this may determine the rate of dopamine synthesis. The present study evaluated L-DOPA inward and outward transfer in immortalized renal proximal tubular epithelial cells of SHR and Wistar-Kyoto rats (WKY). METHODS: Uptake of [(14)C]-L-DOPA was initiated by the addition of 1 mL Hanks' medium with a given concentration of the substrate. The apical fractional outflow of intracellular [(14)C]-L-DOPA was evaluated in cells loaded with [(14)C]-L-DOPA for 6 minutes, and then the corresponding efflux was monitored over 12 minutes. The presence of LAT1 and LAT2 transcripts and protein in WKY and SHR cells was examined, respectively, by reverse transcription-polymerase chain reaction (RT-PCR) and immunobloting. RESULTS: LAT2 in WKY cells contributed almost exclusively for [(14)C]-L-DOPA uptake. In SHR cells [(14)C]-L-DOPA uptake was 25% through system B(0), 25% through LAT2 (resulting from inhibition by 1 mmol/L glycine, L-alanine, L-serine, and L-threonine), and the remaining 50% through LAT1. The efflux of [(14)C]-L-DOPA from WKY and SHR cells corresponded to approximately 65% and approximately 25%, respectively, of the amount accumulated in the cells. The LAT1 and LAT2 transcripts were present in both SHR and WKY cells, but the abundance of both LAT1 and LAT2 proteins in SHR cells was greater than in WKY cells. CONCLUSION: Differences in L-DOPA handling between SHR and WKY cells may result from over-expression of LAT1 and LAT2 transporters in the former. The unique role of Na(+)-dependent transporters (system B(0)) in SHR cells also contributes to the enhanced L-DOPA uptake in these cells.

Amino Acid Transport System y+↗

PubMed2004

D1 dopamine receptor signaling involves caveolin-2 in HEK-293 cells.

BACKGROUND: Dopamine receptors in the kidney, especially those belonging to the D1-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 D1 dopamine receptor (D1R) and signaling molecules are regulated by caveolin in caveolae or lipid rafts. METHODS: Six experimental approaches were used: (1) construction of tagged human D1Rs (hD1Rs) 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: hD1Rs, 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 hD1Rs cofractionated with caveolin-2, G protein subunits, and several signaling molecules. Both exogenously expressed hD1Rs and endogenously expressed rat D1Rs colocalized and coimmunoprecipitated with caveolin-2. A D1R agonist (fenoldopam) increased the amount of caveolin-2beta associated with hD1Rs 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 hD1Rs are distributed in lipid rafts. Heterologously and endogenously expressed D1Rs in renal cells are associated with and regulated by caveolin-2.

Adenylyl Cyclases↗

PubMed2004

Multilocus analysis of hypertension: a hierarchical approach.

While hypertension is a complex disease with a well-documented genetic component, genetic studies often fail to replicate findings. One possibility for such inconsistency is that the underlying genetics of hypertension is not based on single genes of major effect, but on interactions among genes. To test this hypothesis, we studied both single locus and multilocus effects, using a case-control design of subjects from Ghana. Thirteen polymorphisms in eight candidate genes were studied. Each candidate gene has been shown to play a physiological role in blood pressure regulation and affects one of four pathways that modulate blood pressure: vasoconstriction (angiotensinogen, angiotensin converting enzyme - ACE, angiotensin II receptor), nitric oxide (NO) dependent and NO independent vasodilation pathways and sodium balance (G protein-coupled receptor kinase, GRK4). We evaluated single site allelic and genotypic associations, multilocus genotype equilibrium and multilocus genotype associations, using multifactor dimensionality reduction (MDR). For MDR, we performed systematic reanalysis of the data to address the role of various physiological pathways. We found no significant single site associations, but the hypertensive class deviated significantly from genotype equilibrium in more than 25% of all multilocus comparisons (2,162 of 8,178), whereas the normotensive class rarely did (11 of 8,178). The MDR analysis identified a two-locus model including ACE and GRK4 that successfully predicted blood pressure phenotype 70.5% of the time. Thus, our data indicate epistatic interactions play a major role in hypertension susceptibility. Our data also support a model where multiple pathways need to be affected in order to predispose to hypertension.

Alleles↗

PubMed2004

The developing kidney and environmental toxins.

The effects of environmental chemicals, drugs, and physical agents on the developing kidney are influenced by the state of renal development and maturation. The development of the kidney, the major excretory organ after birth, consists of 3 stages: the pronephros, or cervical kidney; mesonephros, or thoracic kidney; and metanephros, or abdominal kidney, the definitive kidney. In humans, nephrogenesis and organogenesis occur from the 6th to the 36th weeks of gestational age. After 36 weeks, nephrogenesis is complete and each kidney has a full complement of nephrons. The extent of chemical-induced renal toxicity is related, in part, to the efficiency in which the particular compound is transported by renal tubules. Because renal tubular transport capacities vary with maturation, the degree of nephrotoxicity may also vary with maturation. The signs and symptoms of nephrotoxicity can appear acutely or insidiously. Unexplained acute renal failure, chronic mild proteinuria, or even hypertension can be a manifestation of nephrotoxic agents. Species differences occur, thus the need for studies in humans.

Animals↗

PubMed2003

Lack of association between the G protein beta3 subunit gene and essential hypertension in Chinese: a case-control and a family-based study.

A C825T polymorphism of the gene encoding the G protein beta3 subunit (GNB3) is associated with enhanced G protein activity and increased intracellular signal transduction. The 825T allele has been implicated in the development of hypertension in some ethnic groups, especially in whites. Studies in Asians and blacks are more controversial, and little information is available on this polymorphism in the susceptibility to hypertension in the Chinese population. Furthermore, the inconsistency between studies may be due to genetic heterogeneity of the population selected and/or the lack of statistical power. We investigated the relationship of this polymorphism with hypertension in two independent northern Chinese populations using both a case-control and a family-based study design. The GNB3 C825T polymorphism was determined by polymerase chain reaction and restriction enzyme digestion. In the case-control study which included 585 hypertensive case subjects and 580 normotensive control subjects there was no significant association between the polymorphism and hypertension status or blood pressure levels. The lack of association was confirmed by the results obtained in 181 hypertensive families using both transmission disequilibrium test and sib transmission disequilibrium test. No preferential transmission was observed for the GNB3 825T allele to the affected subjects. Furthermore, there was no significant association between the polymorphism and body mass index in the case-control study. Therefore our work does not provide evidence in favor of GNB3 C825T being a candidate gene for conferring genetic susceptibility to hypertension or obesity in northern Chinese population.

Blood Pressure↗