Abstract 089: Dopamine D 2 Receptor is Associated with Inverse Salt Sensitivity

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Peng Xu ◽  
John J Gildea ◽  
Pedro A Jose ◽  
Robert M Carey ◽  
Robin A Felder
Keyword(s):  
Blood Pressure ◽  
Kidney Tissue ◽  
Human Kidney ◽  
Salt Sensitivity ◽  
T Test ◽  
Receptor Expression ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
Tissue Slices ◽  
Type D

Our previous studies of salt sensitivity of blood pressure have demonstrated that approximately 11% of study participants have a paradoxical increase in blood pressure (> or = to 7-mm Hg) on a low NaCl diet (defined as inverse salt sensitivity (ISS)). However the mechanisms responsible for this effect are not known. We demonstrated that single nucleotide polymorphisms (SNPs) in the dopamine type 2 receptor (D 2 R) (RS6276 and 6267) are highly associated with ISS ( P values of 1.0х10 –2 and 3.8х10 –2 with odds ratios of 0.32 and 0.48 in unadjusted regression models, respectively). The C allele at both sites confers protection. The D 2 R is strongly expressed throughout the cytoplasm of proximal tubule cells in human kidney tissue slices. We also cultured RPTC from the urine from 4 salt resistant (SR) and 3 ISS participants enrolled in our clinical salt sensitivity studies. We hypothesize that D 2 R containing SNPs have altered receptor expression, and altered signaling compared to wild type controls. ISS participants were homozygous variant for the two D 2 R alleles and showed more D 2 R expression than SR RPTC heterozygous variant (HV) for the two alleles (ISS: 1.166±0.059 n=3 vs SR: 0.969±0.024 n=4, P<0.05, t-test). D 2 R expression was increased when the ISS cells were stimulated by a non-selective D 2 R agonist bromocriptine to a greater extent in the D 2 R SNP cell lines (ISS: VEH 1.166±0.059, vs bromocriptine 1.474 ± 0.040, n=3, P<0.05, t-test). Using the ROS reagent assay, dihydroethidium, there was found to be more ROS products in ISS cells than SR cells when stimulated under low salt (ISS: 1.145 ± 0.053, n=3 vs SR: 0.722 ± 0.101, n=4, P<0.05, t-test). We used a highly selective D 2 R agonist (sumanirole) to stimulate wild-type and SNPed cells, and the results demonstrated no effect in the cells with wild type D 2 R but an increase in ROS in cells heterozygous for the D 2 R SNPs (SNP: VEH 38,364±1,266, sumanirole 50,926 ± 3,310, VS WT: VEH 34,562±1,831 sumanirole 34,435 ± 1,614 RFU n=12, P<0.05, t-test) consistent with the higher expression of D 2 R found in ISS urine cells. We hypothesize that SNPs in the D 2 R lead to increased reactive oxygen species which has previously been associated with renal fibrosis and hypertension.

scholarly journals Hypertension induces glomerulosclerosis in phospholipase C-ε1 deficiency

2020 ◽  
Vol 318 (5) ◽  
pp. F1177-F1187 ◽  
Author(s):  
Douglas K. Atchison ◽  
Christopher L. O’Connor ◽  
Rajasree Menon ◽  
Edgar A. Otto ◽  
Santhi K. Ganesh ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Phospholipase C ◽  
Kidney Tissue ◽  
Human Kidney ◽  
Ang Ii ◽  
Loss Of Function ◽  
Wild Type ◽  
Podocyte Loss ◽  
Deficient Mice ◽  
Glomerular Damage

Loss-of-function mutations in phospholipase C-ε1 (PLCE1) have been detected in patients with nephrotic syndrome, but other family members with the same mutation were asymptomatic, suggesting additional stressor are required to cause the full phenotype. Consistent with these observations, we determined that global Plce1-deficient mice have histologically normal glomeruli and no albuminuria at baseline. Angiotensin II (ANG II) is known to induce glomerular damage in genetically susceptible individuals. Therefore, we tested whether ANG II enhances glomerular damage in Plce1-deficient mice. ANG II increased blood pressure equally in Plce1-deficient and wild-type littermates. Additionally, it led to 20-fold increased albuminuria and significantly more sclerotic glomeruli in Plce1-deficient mice compared with wild-type littermates. Furthermore, Plce1-deficient mice demonstrated diffuse mesangial expansion, podocyte loss, and focal podocyte foot process effacement. To determine whether these effects are mediated by hypertension and hyperfiltration, rather than directly through ANG II, we raised blood pressure to a similar level using DOCA + salt + uninephrectomy and norepinephrine. This caused a fivefold increase in albuminuria in Plce1-deficient mice and a significant increase in the number of sclerotic glomeruli. Consistent with previous findings in mice, we detected strong PLCE1 transcript expression in podocytes using single cell sequencing of human kidney tissue. In hemagglutinin-tagged Plce1 transgenic mice, Plce1 was detected in podocytes and also in glomerular arterioles using immunohistochemistry. Our data demonstrate that Plce1 deficiency in mice predisposes to glomerular damage secondary to hypertensive insults.

Abstract P010: D 1 R And D 5 R And Their Role In The Etiology Of Inverse Salt Sensitivity Of Blood Pressure

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
John J Gildea ◽  
Michael G Daley ◽  
Peng Xu ◽  
Katherine A Schiermeyer ◽  
Wei Yue ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Salt Sensitivity ◽  
T Test ◽  
Morbidity And Mortality ◽  
The Novel ◽  
Proximal Tubule Cells ◽  
Mortality And Morbidity ◽  
R And D ◽  
Low Sodium ◽  
Renal Proximal Tubule Cells

Cardiovascular studies show increased morbidity and mortality in individuals consuming low sodium diets as well as high salt diets. The incidence of salt sensitivity of blood pressure (SS) in normotensives is approximately 18%, causing similar mortality and morbidity as hypertensives. Paradoxically, approximately 15% of normotensives demonstrate an increase in blood pressure on low sodium diets, known as inverse salt sensitivity (ISS). However, little is known about the morbidity and mortality associated with ISS, let alone the mechanisms behind this condition. Since dopamine regulates up to 75% of renal sodium handling, we hypothesized that the dopamine 1 and 5 receptors (D1R, D5R) were involved with the etiology of ISS. Using renal proximal tubule cells (RPTC) isolated from salt diet participant’s urine exposed to 90 mM salt (NaCl) (2 hr), we demonstrated reduced binding of the non-cell permeable D1-like antagonist (D1R and D5R) bodipy-530 SKF83566 (Fl-SKF) in the ISS RPTC when compared to salt resistant (SR) RPTC (ISS -13.9 ± 3.8% vs SR -1.1 ± 3.2%, n=12, p<0.05, t-test). Incubation in 190 mM NaCl for 2 hours and overnight (ON) increased Fl-SKF binding only in the ISS RPTCs but not the SR RPTC when compared to 140 mM NaCl (NS) (ISS 2 Hours +16.6 ± 6.2% and ISS ON +12.0 ± 2.8%, n=12, p<0.05 vs NS, t-test). ON incubation in 90 mM NaCl reduced Fl-SKF binding in both ISS and SR RPTC (ISS -15.2 ± 2.9% and SR -16.3 ± 2.3%, n=12, p<0.01, vs NS, t-test), and this effect was completely blocked by co-incubation with the angiotensin type 1 receptor (AT1R) antagonist losartan (LOS, 1 uM). The decrease in Fl-SKF binding in 90 mM NaCl was attributed to the D5R, and an increase in FL-SKF binding in 190 mM NaCl was verified to be due to an increase in plasma membrane D1R expression using antibodies directed to extracellular epitopes. A D5R specific monoclonal antibody developed in-house binds to the third extracellular loop of this receptor in order to measure these receptors selectively. Continued studies will be conducted with these cell lines with D1R and D5R knocked down to determine specific roles these receptors have in the novel ISS phenotype.

scholarly journals IL23RandIL12BSNPs and Haplotypes Strongly Associate with Crohn's Disease Risk in a New Zealand Population

2010 ◽  
Vol 2010 ◽  
pp. 1-12 ◽  
Author(s):  
Lynnette R. Ferguson ◽  
Dug Yeo Han ◽  
Alan G. Fraser ◽  
Claudia Huebner ◽  
Wen Jiun Lam ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
New Zealand ◽  
Crohn's Disease ◽  
Bowel Resection ◽  
Disease Risk ◽  
Normal Population ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
Single Nucleotide ◽  
Type D

DNA samples from 339 Crohn's disease (CD) and 407 randomly selected controls from the Auckland (New Zealand) IBD project, were genotyped for five common single nucleotide polymorphisms inIL-23R(rs11805303, rs7517847, rs1343151, rs11209026, and rs10889677) and two inIL-12B(rs1363670 and rs6887695). While theIL-12Bvariants did not show an overall association and otherIL23Rvariants led to minor changes in the risk of CD, rs1343151 and/or rs7517847 variants in theIL-23Rgene strongly reduced the risk of developing CD at both allelic and genotype levels. A significantly decreased risk of first diagnosis of childhood CD was observed in individuals carrying the A allele of rs1343151, or between 17–40 y in individuals carrying the G allele in rs7517847 ofIL-23R. A significantly decreased risk of ileocolonic or structuring disease was observed in individuals carrying the A allele in either rs11209026 or rs1343151, or the G allele in rs7517847 ofIL-23R, and when such individuals did develop the disease, they were unlikely to require a bowel resection. Certain haplotypes very strongly modified risk. There was evidence for interactions ofIL-23Rvariants with theNOD2wild-type (d/d) genotype. Down-regulating the function of theIL-23Rgene may decrease CD risk in the normal population.

scholarly journals Effects of environmental and genetic risk factors for salt sensitivity on blood pressure in northern China: the systemic epidemiology of salt sensitivity (EpiSS) cohort study

BMJ Open ◽  
2018 ◽  
Vol 8 (12) ◽  
pp. e023042 ◽  
Author(s):  
Han Qi ◽  
Bin Liu ◽  
Chunyue Guo ◽  
Zheng Liu ◽  
Han Cao ◽  
...  
Keyword(s):  
Risk Factors ◽  
Blood Pressure ◽  
Northern China ◽  
Salt Sensitivity ◽  
Urine Samples ◽  
Liaoning Province ◽  
Nucleotide Polymorphisms ◽  
Spot Urine ◽  
Face To Face ◽  
Non Coding Rnas

PurposeThe systemic epidemiology of salt sensitivity (EpiSS) study aims to combine molecular biology, epidemiology and bioinformatics methods to discover the potential causes of salt sensitivity of blood pressure (SSBP) using single-nucleotide polymorphisms in the genome and non-coding RNAs in the transcriptome to uncover both the genetic and environmental factors of SSBP.ParticipantsBetween July 2014 and July 2016, we enrolled adults from 11 study centres in Beijing and Liaoning Province; participants were of the Han population and were 35–70 years of age. We collected blood samples, spot urine samples and 24-hour urine samples, in addition to baseline data on demographics, health-related lifestyle factors, chronic diseases, family history of illness and anthropometric information through face-to-face interviews using a standardised questionnaire. EpiSS uses the modified Sullivan’s acute oral saline load and diuresis shrinkage test (MSAOSL-DST) to evaluate the effects of salt on blood pressure.Findings to dateIn total, 2163 participants were included in the EpiSS, of which 2144 participants completed the questionnaire, 2120 (98.0%) completed the MSAOSL-DST and 2083 (96.3%) provided a 24-hour urine sample. A total of 2057 participants (1501 women and 556 men) completed all the steps of the investigation and were included in the analysis. Among them, 583 (28.3%) subjects were classified as having salt sensitivity of blood pressure, and 1061 (51.6%) had hypertension.Future plansThe next step of our study is to evaluate the incidence of cardiovascular disease in the participants. Biennial follow-up, including face-to-face questionnaire surveys, laboratory measurements of blood, urinary creatinine, glomerular filtration rate and anthropometric measurements, will occur two additional times. DNA and RNA will be collected for subsequent genetic biomarker studies. We plan on screening the salt-sensitive-related gene loci and non-coding RNAs based on relative environmental risk factors.Trial registration numberChiCTR-EOC-16009980; Pre-results.

Abstract P242: Role of Human Renal Proximal Tubule Sodium Bicarbonate Cotransporter NBCe2 (SLC4A5) in Salt Sensitivity of Blood Pressure

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
John J Gildea ◽  
Julia M Carlson ◽  
Tran T Hanh ◽  
Dora Bigler Wang ◽  
Peng Xu ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Sodium Bicarbonate ◽  
Sodium Transport ◽  
Renal Tissue ◽  
Salt Sensitivity ◽  
Bicarbonate Transport ◽  
Nucleotide Polymorphisms ◽  
High Sodium ◽  
Sodium Bicarbonate Cotransporter ◽  
Renal Tubular

The sodium bicarbonate cotransporter NBCe2 (encoded by SLC4A5) partially regulates renal tubular sodium bicarbonate transport. Hypothesis: since SLC4A5 single nucleotide polymorphisms (SNPs, rs10177833 and rs7571842) are associated with salt sensitivity of blood pressure, the gene product, NBCe2, would be involved with the etiology of human salt sensitivity. NBCe2 was localized in freshly fixed renal tissue and in primary and immortalized RPT cell (RPTC) cultures from tissue or isolated from urine. Basal expression of NBCe2 mRNA and protein was not different between RPTCs carrying WT or HV SLC4A5 before or after dopaminergic or angiotensin (II and III) stimulation. However, total transcellular sodium transport, NHE3 protein expression, and Cl-/HCO3- exchanger activity were higher in SLC4A5 HV than WT RPTCs (WT: 8.6±1.2 mM NaCl n=6, 5207.1±386.4 RFU n=36, 0.265±0.006 pH unit/min, n=33 respectively; VS HV: 14.75±0.7 mM NaCl n=4, 6946.2±500.4 RFU n=48, 0.314±0.018 pH unit/min n=35 respectively, p<0.01). Aberrant sodium transport was even more evident after increasing intracellular sodium, which resulted in increased NBCe2 mRNA, NBCe2 protein and bicarbonate transport in HV RPTCs compared to WT (WT 146% ± 24% , 109% ± 4.7%, 89% ± 4.5%, respectively, VS HV 214% ± 23%, 128% ± 5.7%, 141% ± 4.8%, respectively N=8-12, p<0.05). RPTCs carrying HV variants showed increased binding of HNF4A to SLC4A5 DNA, which was blocked by two HNF4A antagonists. Assays in RPTCs isolated from urine showed increased bicarbonate-dependent pH recovery in RPTCs from salt-sensitive subjects who are HV for SLC4A5. NBCe2 under high sodium is hyper-responsive in RPTCs carrying SLC4A5 HV through an aberrant HNF4A-mediated mechanism.

Abstract 12: The Etiology Of Inverse Salt Sensitivity Of Blood Pressure: Mirna-485-5p Binds To The Dopamine Type 2 Receptor (d 2 R) Snp Rs6276 And Decreases D 2 R Expression

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
John J Gildea ◽  
Peng Xu ◽  
Katherine Schiermeyer ◽  
Wei Yue ◽  
Robert M Carey ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cell Lines ◽  
Salt Sensitivity ◽  
Wild Type ◽  
Binding Studies ◽  
Mirna Mimic ◽  
Low Sodium Diet ◽  
Renal Proximal Tubule Cells ◽  
20 Nm ◽  
Cell Phenotypes

Inverse salt sensitivity is the paradoxical increase in blood pressure of individuals to a low sodium diet. rs6276, a single nucleotide polymorphism found in the 3’ untranslated region of the D2R gene (DRD2), which is associated with decreased expression and is also associated with the inverse salt sensitive phenotype (ISS). Urine derived renal proximal tubule cells grown from ISS participants with homozygous rs6276 SNPs vs salt resistant (SR) wild type for rs6276 SNPs have decreased expression of D2R as measured by receptor binding studies using BodipyFL-Spiperone (100 nM for 2 hrs, -36.9% ± 2.6% reduction in ISS-10 vs SR-6, n=5, p<0.01). miRNA-485-5p potentially binds to the rs6276 SNP in the 3’ UTR site and therefore could be a member of a newly identified classification of SNPs called miRSNPs. We transfected a miRNA-485-5p miRNA mimic and a miRNA blocker (20 nM for 72 hrs) to determine the effect on D2R expression on both wild type and homozygous variant SNP participant cell lines. Transfection of mir-485-5p only alters the expression of D2R in the ISS cell lines with SNPs (52619 ± 2001 RFU ISS control miRNA vs 69496 ± 2108 RFU ISS-10 miRNA blocker and vs 30434 ± 1824 RFU ISS-10 miRNA mimic, n=9, p<0.01, one-way ANOVA). The miRNA-485-5p blocker was able to return the D2R expression levels back to levels found in SR cells. Further studies are necessary to determine if the miRNA-485-5p mimic enhances and miRNA-485-5p blocker reverses any of the ISS cell phenotypes identified.

Hypotension in NKCC1 null mice: role of the kidneys

2006 ◽  
Vol 290 (2) ◽  
pp. F409-F416 ◽  
Author(s):  
Susan M. Wall ◽  
Mark A. Knepper ◽  
Kathryn A. Hassell ◽  
Michael P. Fischer ◽  
Adetola Shodeinde ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Kidney Tissue ◽  
Free Water ◽  
Plasma Renin ◽  
Wild Type ◽  
Deficient Diet ◽  
Water Excretion ◽  
Α Subunit ◽  
Serum Aldosterone ◽  
Transporter Expression

NKCC1 null mice are hypotensive, in part, from the absence of NKCC1-mediated vasoconstriction. Whether these mice have renal defects in NaCl and water handling which contribute to the hypotension is unexplored. Therefore, we asked 1) whether NKCC1 ( −/−) mice have a defect in the regulation of NaCl and water balance, which might contribute to the observed hypotension and 2) whether the hypotension observed in these mice is accompanied by endocrine abnormalities and/or downregulation of renal Na+ transporter expression. Thus we performed balance studies, semiquantitative immunoblotting, and immunohistochemistry of kidney tissue from NKCC1 ( +/+) and NKCC1 ( −/−) mice which consumed either a high (2.8% NaCl)- or a low-NaCl (0.01% NaCl) diet for 7 days. Blood pressure was lower in NKCC1 ( −/−) than NKCC1 ( +/+) mice following either high or low dietary NaCl intake. Relative to wild-type mice, NKCC1 null mice had a lower plasma ANP concentration, a higher plasma renin and a higher serum K+ concentration with inappropriately low urinary K+ excretion, although serum aldosterone was either the same or only slightly increased in the mutant mice. Expression of NHE3, the α-subunit of the Na-K-ATPase, NCC, and NKCC2 were higher in NKCC1 null than in wild-type mice, although differences were generally greater during NaCl restriction. NKCC1 null mice had a reduced capacity to excrete free water than wild-type mice, which resulted in hypochloremia following the NaCl-deficient diet. Hypochloremia did not occur from increased aquaporin-1 (AQP1) or 2 protein expression or from redistribution of AQP2 to the apical regions of principal cells. Instead, NKCC1 null mice had a blunted increase in urinary osmolality following vasopressin administration, which should increase free water excretion and attenuate the hypochloremia. In conclusion, aldosterone release is inappropriately low in NKCC1 null mice. Moreover, the action of aldosterone and vasopressin is altered within kidneys of NKCC1 null mice, which likely contributes to their hypotension. Increased Na+ transporter expression, increased plasma renin, and reduced plasma ANP, as observed in NKCC1 null mice, should increase vascular volume and blood pressure, thus minimizing hypotension.

scholarly journals Striatin heterozygous mice are more sensitive to aldosterone-induced injury

2020 ◽  
Vol 245 (3) ◽  
pp. 439-450
Author(s):  
Amanda E Garza ◽  
Elijah Trefts ◽  
Isis A Katayama Rangel ◽  
Danielle Brooks ◽  
Rene Baudrand ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Epithelial Cells ◽  
Active Treatment ◽  
Mineralocorticoid Receptor ◽  
Renal Damage ◽  
Kidney Tissue ◽  
Macrophage Infiltration ◽  
Male Mice ◽  
Wild Type ◽  
Second Messenger Signaling

Aldosterone modulates the activity of both epithelial (specifically renal) and non-epithelial cells. Binding to the mineralocorticoid receptor (MR), activates two pathways: the classical genomic and the rapidly activated non-genomic that is substantially modulated by the level of striatin. We hypothesized that disruption of MR’s non-genomic pathway would alter aldosterone-induced cardiovascular/renal damage. To test this hypothesis, wild type (WT) and striatin heterozygous knockout (Strn+/−) littermate male mice were fed a liberal sodium (1.6% Na+) diet and randomized to either protocol one: 3 weeks of treatment with either vehicle or aldosterone plus/minus MR antagonists, eplerenone or esaxerenone or protocol two: 2 weeks of treatment with either vehicle or L-NAME/AngII plus/minus MR antagonists, spironolactone or esaxerenone. Compared to the WT mice, basally, the Strn+/− mice had greater (~26%) estimated renal glomeruli volume and reduced non-genomic second messenger signaling (pAkt/Akt ratio) in kidney tissue. In response to active treatment, the striatin-associated-cardiovascular/renal damage was limited to volume effects induced by aldosterone infusion: significantly increased blood pressure (BP) and albuminuria. In contrast, with aldosterone or L-NAME/AngII treatment, striatin deficiency did not modify aldosterone-mediated damage: in the heart and kidney, macrophage infiltration, and increases in aldosterone-induced biomarkers of injury. All changes were near-normalized following MR blockade with spironolactone or esaxerenone, except increased BP in the L-NAME/AngII model. In conclusion, the loss of striatin amplified aldosterone-induced damage suggesting that aldosterone’s non-genomic pathway is protective but only related to effects likely mediated via epithelial, but not non-epithelial cells.

scholarly journals Deficiency of MicroRNA-181a Results in Transcriptome-Wide Cell Specific Changes in the Kidney that Lead to Elevated Blood Pressure and Salt Sensitivity

2021 ◽  
Author(s):  
Madeleine R. Paterson ◽  
Kristy L. Jackson ◽  
Malathi I. Dona ◽  
Gabriella E. Farrugia ◽  
Bruna Visniauskas ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Knockout Mice ◽  
Molecular Mechanisms ◽  
Salt Sensitivity ◽  
Juxtaglomerular Cells ◽  
Renal Cells ◽  
Wild Type ◽  
Knockout Mouse Model

AbstractMicroRNA miR-181a is down-regulated in the kidneys of hypertensive patients and hypertensive mice. In vitro, miR-181a is a posttranslational inhibitor of renin expression, but pleiotropic mechanisms by which miR-181a may influence blood pressure (BP) are unknown. Here we determined whether deletion of miR-181a/b-1 in vivo changes BP and the molecular mechanisms involved at the single-cell level. We developed a knockout mouse model lacking miR-181a/b-1 genes using CRISPR/Cas9 technology. Radio-telemetry probes were implanted in twelve-week-old C57BL/6J wild-type and miR-181a/b-1 knockout mice. Systolic and diastolic BP were 4-5mmHg higher in knockout compared with wild-type mice over 24-hours (P<0.01). Compared with wild-type mice, renal renin was higher in the juxtaglomerular cells of knockout mice. BP was similar in wild-type mice on a high (3.1%) versus low (0.3%) sodium diet (+0.4±0.8mmHg) but knockout mice showed salt sensitivity (+3.3±0.8mmHg, P<0.001). Since microRNAs can target several mRNAs simultaneously, we performed single-nuclei RNA-sequencing in 6,699 renal cells. We identified 12 distinct types of renal cells, all of which had genes that were dysregulated. This included genes involved in renal fibrosis and inflammation such as Stat4, Col4a1, Cd81, Flt3l, Cxcl16, Smad4. We observed up-regulation of pathways related to the immune system, inflammatory response, reactive oxygen species and nerve development, consistent with higher tyrosine hydroxylase. In conclusion, downregulation of the miR-181a gene led to increased BP and salt sensitivity in mice. This is likely due to an increase in renin expression in juxtaglomerular cells, as well as microRNA-driven pleiotropic effects impacting renal pathways associated with hypertension.

Gene deletion of P2Y4 receptor lowers exercise capacity and reduces myocardial hypertrophy with swimming exercise

2012 ◽  
Vol 303 (7) ◽  
pp. H835-H843 ◽  
Author(s):  
Michael Horckmans ◽  
Elvira Léon-Gómez ◽  
Bernard Robaye ◽  
Jean-Luc Balligand ◽  
Jean-Marie Boeynaems ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Cardiac Hypertrophy ◽  
Open Field ◽  
Exercise Capacity ◽  
Prolonged Exercise ◽  
Receptor Expression ◽  
Tail Suspension ◽  
Wild Type ◽  
Exercise Induced

Nucleotides released within the heart under pathological conditions can be involved in cardioprotection or cardiac fibrosis through the activation purinergic P2Y2 and P2Y6 receptors, respectively. We previously demonstrated that adult P2Y4-null mice display a microcardia phenotype related to a cardiac angiogenic defect. To evaluate the functional consequences of this defect, we performed here a combination of cardiac monitoring and exercise tests. We investigated the exercise capacity of P2Y4 wild-type and P2Y4-null mice in forced swimming and running tests. Analysis of their stress, locomotion, and resignation was realized in open field, black and white box, and tail suspension experiments. Exercise-induced cardiac hypertrophy was evaluated after repeated and prolonged exercise in P2Y4 wild-type and P2Y4-null hearts. We showed that P2Y4-null mice have a lower exercise capacity in both swimming and treadmill tests. This was not related to decreased motivation or increased stress, since open field, white and black box, and mouse tail suspension tests gave comparable results in P2Y4 wild-type and P2Y4-null mice. Heart rate and blood pressure rose normally in P2Y4-null swimming mice equipped with a telemetric implant. On the contrary, we observed a delayed recovery of postexercise blood pressure after exercise in P2Y4-null mice. The heart rate increment in response to catecholamines was also similar in P2Y4 wild-type and P2Y4-null implanted mice, which is consistent with a similar level of cardiac β-receptor expression. Interestingly, the heart of P2Y4-null mice displayed a reduced sympathetic innervation associated with a decreased norepinephrine level. We also demonstrated that exercise-induced cardiac hypertrophy was lower in P2Y4-null mice after repeated and prolonged exercise. This was associated with a lower increase in cardiomyocyte size and microvessel density. In conclusion, besides its role in cardiac development, P2Y4 receptor could constitute an important regulator of acute and chronic response to exercise.

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