Multiple blood pressure loci on rat chromosome 13 attenuate development of hypertension in the Dahl S hypertensive rat

2007 ◽  
Vol 31 (2) ◽  
pp. 228-235 ◽  
Author(s):  
Carol Moreno ◽  
Mary L. Kaldunski ◽  
Tao Wang ◽  
Richard J. Roman ◽  
Andrew S. Greene ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Damage ◽  
High Salt ◽  
Male Rats ◽  
Brown Norway ◽  
High Salt Diet ◽  
Salt Diet ◽  
Chromosome 13 ◽  
Congenic Strains ◽  
Multiple Blood

Previous studies have indicated that substitution of chromosome 13 of the salt-resistant Brown Norway BN/SsNHsdMcwi (BN) rat into the genomic background of the Dahl salt-sensitive SS/JrHsdMcwi (SS) rat attenuates the development of salt-sensitive hypertension and renal damage. To identify the regions within chromosome 13 that attenuate the development of hypertension during a high-salt diet in the SS rat, we phenotyped a series of overlapping congenic lines covering chromosome 13, generated from an intercross between the consomic SS-13BN rat and the SS rat. Blood pressure was determined in chronically catheterized rats after 2 wk of high-salt diet (8% NaCl) together with microalbuminuria as an index of renal damage. Four discrete regions were identified, ranging in size from 4.5 to 16 Mbp, each of which independently provided significant protection from hypertension during high-salt diet, reducing blood pressure by 20–29 mmHg. Protection was more robust in female than male rats in some of the congenic strains, suggesting a sex interaction with some of the genes determining blood pressure during high-salt diet. Among the 23 congenic strains, several regions overlapped. When three of the “protective” regions were combined onto one broad congenic strain, no summation effect was seen, obtaining the same decrease in blood pressure as with each one independently. We conclude from these studies that there are four regions within chromosome 13 containing genes that interact epistatically and influence arterial pressure.

Abstract P149: Bilateral Renal Denervation Attenuates Hypertension in Male Rats Deficient of Functional Endothelin B Receptors but Does Not Affect Salt-Sensitivity

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Bryan K Becker ◽  
Amanda C Feagans ◽  
Chunhua Jin ◽  
David M Pollock
Keyword(s):  
Blood Pressure ◽  
Total Protein ◽  
Renal Denervation ◽  
High Salt ◽  
Male Rats ◽  
Renal Nerves ◽  
High Salt Diet ◽  
Salt Diet ◽  
Endothelin B ◽  
Renal Sympathetic

Independent studies of renal sympathetic nerves and the endothelin (ET) system have demonstrated important contributions of each in the progression of hypertension. Very few studies, however, have investigated the interaction between the ET system and renal nerves in relation to blood pressure control and electrolyte homeostasis. Although endothelin B (ETB) receptors in the renal medulla promote natriuresis, ETB receptors on sympathetic neurons are thought to increase neuronal activity. We hypothesized that renal denervation reduces blood pressure in a salt-sensitive, hypertensive model of ET dysfunction, the ETB-deficient (ETB-def) rat, which lacks functional ETB receptors in all tissues except neurons. After bilateral renal sympathetic denervation (Dnx) or sham operation of ETB-def and transgenic control (TG) rats, baseline blood pressure was recorded via telemetry for 5 days on a normal salt (0.49% NaCl) diet followed by a high salt (4.0%) diet. At baseline, ETB-def Dnx rats had a lower 24-hr systolic blood pressure (SBP) (152.6 ± 3.6 mmHg) relative to ETB-def sham (167.8 ± 2.6 mmHg; p < 0.005; n = 7/group). Denervation did not significantly affect TG rats relative to sham on normal salt (138.8 ± 2.5 vs. 144.7 ± 0.5 mmHg respectively; p = 0.53; n = 6/group). Following 10 days of high salt diet, ETB-def sham rats had an increased 24-hr SBP (+10.59 ± 2.8 mmHg relative to baseline; p < 0.005). There was a similar increase in SBP in ETB-def Dnx rats (+10.03 ± 2.3 mmHg relative to baseline; p < 0.005), although the ETB-def Dnx group remained lower than ETB-def sham. High salt had no effect on TG sham or Dnx animals (-2.2 ± 1.3 and -0.6 ± 2.8 mmHg relative to baseline). Preliminary evidence from a subset of the animals in this experiment indicated a dramatically reduced inner medullary ET-1 content in ETB-def sham rats vs. TG sham (97.9 ± 15.4 vs. 327.0 ± 25.4 ng/mg total protein; p < 0.005; n = 3-4/group) in both ETB-def and TG groups, Dnx tended to increase inner medullary ET-1 content (181.8 ± 75.8 and 402.7 ± 19.6 ng/mg total protein respectively). We conclude that in a model of ET dysfunction, the renal nerves are integral mediators of hypertension during normal salt diet, but do not mediate the increase in pressure following high salt diet in this model of salt-sensitive hypertension.

Abstract P335: Greater Reduction in Sympathetic Tone following ET B Receptor Blockade in Rats Lacking the Clock Gene Bmal1 during High Salt Diet

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Jermaine G Johnston ◽  
Bryan K Becker ◽  
Chunhua Jin ◽  
David M Pollock
Keyword(s):  
Blood Pressure ◽  
Clock Gene ◽  
Recovery Period ◽  
Sympathetic Tone ◽  
High Salt ◽  
Male Rats ◽  
Receptor Blockade ◽  
High Salt Diet ◽  
Salt Diet ◽  
Cardiovascular Morbidity And Mortality

The absence of diurnal oscillations in blood pressure is associated with increased cardiovascular morbidity and mortality. The clock gene Bmal1 plays important roles in diurnal cardiovascular control as mice lacking Bmal1 have lower blood pressure and lack a diurnal rhythm. Our lab has previously reported a global Bmal1 knockout rat model that lacks a night-day difference in sodium excretion. Due to the importance of endothelin signaling in sodium homeostasis and autonomic tone, we sought to characterize the hemodynamic and autonomic responses of our Bmal1 knockout (KO) rat to high salt diet and endothelin receptor blockade. Male rats homozygous for the Bmal1 mutation (KO, n = 4) and wild type (WT, n = 7) littermate controls were implanted with telemetry transmitters to record blood pressure. After a recovery period of at least one week, the rats were placed on 7 days each of normal salt (0.49% NaCl) diet, high salt (4.0% NaCl) diet, followed by high salt diet containing the specific ET B receptor antagonist A192621 (10 mg/kg/day, p.o.). Rats were placed in metabolic cages for the last three days of each diet. Surprisingly, KO rats had a similar night-day difference in mean arterial pressure (MAP) as WT during normal salt diet (6.3 ± 0.4 vs. 6.9 ± 0.9 mmHg; respectively), high salt diet (7.1 ± 0.1 vs. 5.4 ± 0.9 mmHg; respectively), and high salt + A192621 (5.4 ± 0.4 vs. 4.8 ± 1.1 mmHg; respectively). KO and WT rats had similar 24-hr MAP during normal salt diet (104.1 ± 3.3 vs. 107.3 ± 1.2 mmHg; respectively), high salt diet (113.8 ± 4.1 vs. 114.0 ± 1.4 mmHg; respectively), and high salt + A192621 (136.3 ± 8.6 vs. 133.4 ± 3.1 mmHg; respectively). Despite these similar blood pressure responses to high salt diet and ET B antagonism, KO rats had a significantly greater reduction in vasomotor sympathetic to parasympathetic tone compared to WT rats as demonstrated by low frequency to high frequency (LF/HF) analysis of diastolic blood pressure variability (-0.9 ± 0.3 vs. 0.1 ± 0.2 ΔLF/HF relative to normal salt; respectively; p = 0.01). These results indicate that lack of Bmal1 may result in greater ET B receptor mediated vasomotor sympathetic tone in rats fed a high salt diet and that factors other than Bmal1 may be influential in circadian control of blood pressure in rats.

Abstract P279: Mapping of Chromosome 2 Differentially Expressed Aortic Genes Linked to Vascular Inflammation Using Congenic Rats Fed a High-salt Diet

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Olga Berillo ◽  
Sofiane Ouerd ◽  
Ku-Geng Huo ◽  
Chantal Richer ◽  
Daniel Sinnett ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Vascular Inflammation ◽  
Differential Expression Analysis ◽  
High Salt ◽  
Differentially Expressed ◽  
Brown Norway ◽  
Illumina Hiseq ◽  
High Salt Diet ◽  
Salt Diet ◽  
Total Rna

Background: Three congenic rat strains (SB2a, SB2b and SB2e) were created by chromosome (Chr) 2 fragment introgression from normotensive Brown Norway (BN) rats into hypertensive Dahl salt sensitive (SS) background. SB2a and SB2b rats fed a normal-salt diet presented reduced blood pressure (BP) and inflammation when compared to SS rats. We hypothesized that BN-Chr2 contains antihypertensive and anti-inflammatory genes that could prevent high-salt diet (HSD)-induced BP elevation and vascular injury in SB2a and SB2b rats. These genes will be identified using microRNA (miRNA) and total RNA expression profiling analysis in aorta of congenic rats fed a HSD. Methods and Results: Four-to-6 week-old male SS, SS, SB2a and SB2b rats were fed a HSD (4% NaCl) for 8 weeks or until they developed a stroke as manifested by seizures. Systolic blood pressure (SBP) was measured by telemetry. Systolic BP was higher in SB2b but not SB2a when compared to SS (185±8, 167±7 vs 168±5 mm Hg). Total RNA was extracted from aorta and used to construct libraries for small and total RNA sequencing using Illumina HiSeq-2500. The bioinformatics pipeline included: FastQC for quality control, STAR for genome (Rattus norvegicus, release-86) alignment, mirdeep2 for miRNA annotation and counting, Htseq-count for mRNA and long non-coding RNA annotation and counting; R for differential expression analysis. Differentially expressed miRNAs and genes (mRNAs and non-coding RNAs) were identified in SB2a vs SS (miRNAs: 11 up and 10 down; genes: 92 up and 91 down) and in SB2b vs SS (miRNAs: 3 up and 2 down; genes: 10 up and 13 down) with FDR<0.05. Differentially expressed genes encoded within different BN-Chr2 congenic portions were identified in SB2a vs SS (genes: 7 up and 2 down) and SB2b vs SS (genes: 6 up and 4 down). Conclusions and Perspectives: Differentially expressed BN-Chr2 encoded genes were identified in aorta of congenic SB2a and SB2b rats fed HSD. Whether these genes play a role in HSD-induced BP elevation and vascular inflammation remains to be determined.

scholarly journals Salt-induced sympathoexcitation involves vasopressin V1a receptor activation in the paraventricular nucleus of the hypothalamus

2015 ◽  
Vol 309 (11) ◽  
pp. R1369-R1379 ◽  
Author(s):  
Natalia Ribeiro ◽  
Helena do Nascimento Panizza ◽  
Karoline Martins dos Santos ◽  
Hildebrando C. Ferreira-Neto ◽  
Vagner Roberto Antunes
Keyword(s):  
Blood Pressure ◽  
High Blood Pressure ◽  
Paraventricular Nucleus ◽  
Receptor Activation ◽  
High Salt ◽  
Male Rats ◽  
Plasma Sodium ◽  
High Salt Diet ◽  
Salt Loading ◽  
Salt Diet

A high-salt diet can lead to hydromineral imbalance and increases in plasma sodium and osmolality. It is recognized as one of the major contributing factors for cardiovascular diseases such as hypertension. The paraventricular nucleus (PVN) plays a pivotal role in osmotically driven sympathoexcitation and high blood pressure, the precise mechanisms of which are not fully understood. Recent evidence indicates that AVP released from magnocellular neurons might be involved in this process. Using a combination of in vivo and in situ studies, we sought to investigate whether AVP, acting on PVN neurons, can change mean arterial pressure (MAP) and sympathetic nerve activity (SNA) in euhydrated male rats. Furthermore, we wanted to determine whether V1a receptors on PVN neurons would be involved in salt-induced sympathoexcitation and hypertension. In rats, 4 days of salt loading (NaCl 2%) elicited a significant increase in plasma osmolality (39 ± 7 mosmol/kgH2O), an increase in MAP (26 ± 2 mmHg, P < 0.001), and sympathoexcitation compared with euhydrated rats. Microinjection of AVP into the PVN of conscious euhydrated animals (100 nl, 3 μM) elicited a pressor response (14 ± 2 mmHg) and a significant increase in lumbar SNA (100 nl, 1 mM) (19 ± 5%). Pretreatment with a V1a receptor antagonist, microinjected bilaterally into the PVN of salt-loaded animals, elicited a decrease in lumbar SNA (−14 ± 5%) and MAP (−19 ± 5 mmHg), when compared with the euhydrated group. Our findings show that AVP plays an important role in modulating the salt-induced sympathoexcitation and high blood pressure, via V1a receptors, within the PVN of male rats. As such, V1a receptors in the PVN might contribute to neurogenic hypertension in individuals consuming a high-salt diet.

scholarly journals CCL2 mediates early renal leukocyte infiltration during salt-sensitive hypertension

2020 ◽  
Vol 318 (4) ◽  
pp. F982-F993
Author(s):  
Ammar J. Alsheikh ◽  
John Henry Dasinger ◽  
Justine M. Abais-Battad ◽  
Daniel J. Fehrenbach ◽  
Chun Yang ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Damage ◽  
High Salt ◽  
Leukocyte Infiltration ◽  
Sequencing Data ◽  
Data Set ◽  
High Salt Diet ◽  
Salt Diet ◽  
Salt Sensitive Hypertension

Studies examining mechanisms of Dahl salt-sensitive (SS) hypertension have implicated the infiltration of leukocytes in the kidneys, which contribute to renal disease and elevated blood pressure. However, the signaling pathways by which leukocytes traffic to the kidneys remain poorly understood. The present study nominated a signaling pathway by analyzing a kidney RNA sequencing data set from SS rats fed either a low-salt (0.4% NaCl) diet or a high-salt (4.0% NaCl) diet. From this analysis, chemokine (C-C motif) ligand 2 (CCL2) and chemokine (C-C motif) receptor 2 (CCR2) were nominated as a potential pathway modifying renal leukocyte infiltration and contributing to SS hypertension. The functional role of the CCL2/CCR2 pathway was tested by daily administration of CCR2 antagonist (RS-102895 at 5 mg·kg−1·day−1 in DMSO) or DMSO vehicle for 3 or 21 days by intraperitoneal injections during the high salt challenge. Blood pressure, renal leukocyte infiltration, and renal damage were evaluated. The results demonstrated that RS-102895 treatment ameliorated renal damage (urinary albumin excretion; 43.4 ± 5.1 vs. 114.7 ± 15.2 mg/day in vehicle, P < 0.001) and hypertension (144.3 ± 2.2 vs. 158.9 ± 4.8 mmHg in vehicle, P < 0.001) after 21 days of high-salt diet. It was determined that renal leukocyte infiltration was blunted by day 3 of the high-salt diet (1.4 ± 0.1 vs. 1.9 ± 0.2 in vehicle × 106 CD45+ cells/kidney, P = 0.034). An in vitro chemotaxis assay validated the effect of RS-102895 on leukocyte chemotaxis toward CCL2. The results suggest that increased CCL2 in SS kidneys is important in the early recruitment of leukocytes, and blockade of this recruitment by administering RS-102895 subsequently blunted the renal damage and hypertension.

scholarly journals Gambaran Tekanan Darah Tikus Wistar Jantan dan Betina Setelah Pemberian Diet Tinggi Garam

2013 ◽  
Vol 2 (3) ◽  
pp. 146
Author(s):  
Mutia Lailani ◽  
Zulkarnain Edward ◽  
Rahmatina B Herman
Keyword(s):  
Blood Pressure ◽  
High Salt ◽  
Female Rats ◽  
Male Rats ◽  
Control Group ◽  
Control Group Design ◽  
High Salt Diet ◽  
Salt Diet ◽  
Group Design ◽  
Post Test

AbstrakHipertensi masih menjadi masalah kesehatan di dunia. Penyebabnya diduga berkaitan dengan diet tinggi garam. Tujuan Penelitian ini ialah untuk mengetahui gambaran tekanan darah tikus Wistar setelah pemberian diet tinggigaram. Penelitian ini adalah eksperimental dengan post-test only control group design. Subjek penelitian terdiri dari 10 ekor tikus Wistar jantan dan 10 ekor betina yang dibagi menjadi kelompok kontrol (K) dan kelompok perlakuan (P). Diet tinggi garam (NaCl8%, 3ml/hari) diberikan pada kelompok P selama empat minggu. Hasil penelitian menunjukkan bahwa terjadi peningkatan tekanan darah yang bermakna pada kelompok P bila dibandingkan dengan kelompok K, yaitu tekanan darah sistolik (TDS) 191±17mmHg (P) dan 168±16mmHg (K) (p<0,05), tekanan darah diastolik (TDD) 162±17mmHg (P) dan 139±13mmHg (K) (p<0,05), tekanan arteri rata-rata (TAR) 176±17mmHg (P) dan 156±15mmHg (K) (p<0,05). Peningkatan TDS dan TDD hanya terjadi pada tikus jantan, tidak pada tikus betina. Pada tikus jantan TDS 185±13mmHg (P) dan 159±9mmHg (K) (p<0,05), TDD 159±18mmHg (P) dan 131±10mmHg (K) (p<0,05), TAR 172±16mmHg (P) dan 150±15mmHg (K) (p>0,05). Pada tikus betina TDS 197±19mmHg (P) dan 178±16mmHg (K) (p>0,05), TDD 165±18mmHg (P) dan 148±11mmHg (K) (p>0,05), TAR 181±18mmHg (P) dan 162±14mmHg (K) (p>0,05). Kesimpulan studi ini adalah peningkatan tekanan darah setelah pemberian diet tinggi garam hanya terjadi pada tikus jantan.Kata kunci: diet tinggi garam, tekanan darah, hipertensiAbstractHypertension remains a health problem in the world. The cause is believed to be related to the high-salt diet. The purpose of this studi was to describe the blood pressure of Wistar rats after administration of high-salt diet. This research was experimental with post-test only control group design. Ten male and ten female Wistar rats were divided into two groups: control group(K) and treated group(P). High-salt diet (8%NaCl, 3ml/day) was given to the P group for four weeks. Blood pressure increased significantly in group P compared to group K, systolic blood pressure (SBP) 191±17mmHg (P) and 168±16mmHg (K) in (p<0.05), diastolic blood pressure (DBP) 162±17mmHg (P) and 139±13mmHg (K) in (p<0.05), mean arterial pressure (MAP) 176±17mmHg (P) and 156±15mmHg (K) in (p<0.05). The increase in SBP and DBP only occurred in male rats, not in female rats. In male rats, SBP were 185±13mmHg (P) and 159±9mmHg (K) in (p<0.05), DBP were 159±18mmHg (P) and 131±10mmHg (K) in (p<0.05), MAP were 172±16mmHg (P) and 150±15mmHg (K) in (p>0.05). In female rats, SBP were197±19mmHg (P) and 178±16mmHg (K) in (p>0.05), DBP were 165±18mmHg (P) and 148±11mmHg (K) in (p>0.05), MAP were 181±18mmHg (P) and 162±14mmHg (K) in (p>0.05). The conclusion of this study is an increase of blood pressure after the administration of high-salt diet only occured in male rats.Keywords: high-salt diet, blood pressure, hypertension

scholarly journals Effect of high salt diet on blood pressure and renal damage during vascular endothelial growth factor inhibition with sunitinib

2015 ◽  
Vol 31 (6) ◽  
pp. 914-921 ◽  
Author(s):  
Stephanie Lankhorst ◽  
Hans J. Baelde ◽  
Marian C. Clahsen-van Groningen ◽  
Frank M.M. Smedts ◽  
A.H. Jan Danser ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Renal Damage ◽  
High Salt ◽  
Vascular Endothelial ◽  
High Salt Diet ◽  
Salt Diet ◽  
Endothelial Growth Factor

scholarly journals Effect of cocoa powder on hypertension and antioxidant status in uninephrectomized hypertensive rats

2020 ◽  
Vol 13 (4) ◽  
pp. 695-705
Author(s):  
Olayinka Christianah Jayeola ◽  
Ademola Adetokunbo Oyagbemi ◽  
Omolara Ibiwunmi Okunlola ◽  
Olayiwola Olubamiwa ◽  
Temidayo Olutayo Omobowale ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Antioxidant Status ◽  
Renal Damage ◽  
High Salt ◽  
Hypertensive Rats ◽  
High Salt Diet ◽  
Salt Diet ◽  
Cocoa Powder ◽  
Markers Of Inflammation

Background and Aim: High salt diet and uninephrectomy are associated with high blood pressure with attendant cardiovascular disease conditions such as hypertension, renal damage, myocardial infarction, and stroke. The aim of this study was to investigate the beneficial effects of consumption of cocoa and cocoa-containing products in the management of high blood pressure in uninephrectomized hypertensive rats. Materials and Methods: The effect of cocoa powder on blood pressure, markers of inflammation, oxidative stress, and histopathology were investigated in uninephrectomized animals fed with cocoa feed alone or in combination with a high salt diet. Male rats were randomly divided into five groups: Group A was the control group and fed with normal feed alone, Group B was fed with cocoa feed alone, Group C was fed with high salt diet (8% salt), Group D was fed with cocoa-feed compounded with 8% salt for 4 weeks after uninephrectomy, and Group E was uninephrectomized rats on a normal diet. The left kidneys of animals in Groups C, D, and E were removed by surgery. After 4 weeks of treatment, the systolic, diastolic, and mean arterial blood pressure was measured. The serum markers of renal damage and oxidative stress were determined. Histological examination was also performed on renal and cardiac tissues. Results: Results showed significant increases in biomarkers of oxidative stress, inflammation, and renal damage with a concomitant decrease in antioxidant status in hypertensive uninephrectomized rats. Cocoa feed, however, significantly improved blood pressure and nitric oxide bioavailability, antioxidant status and reduced markers of inflammation and oxidative stress. Conclusion: These findings show that cocoa powder could be used to maintain blood pressure levels in hypertensive rats through its antioxidant capacity.

Transfer of Brown Norway Rat Chromosome 13 into Dahl S Genomic Background Confers Protection from High Salt Diet

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 717-717
Author(s):  
Allen W Cowley ◽  
Richard J Roman ◽  
Mary L Kaldunski ◽  
Peter J Tonellato ◽  
Pierre Dumas ◽  
...  
Keyword(s):  
Complex Traits ◽  
Salt Intake ◽  
High Salt ◽  
Brown Norway ◽  
High Salt Diet ◽  
Salt Diet ◽  
Chromosome 13 ◽  
Protein Excretion ◽  
High Salt Intake ◽  
Renal Histology

P132 Consomic rats (SS BN13 ) were bred in which chromosome 13 from normotensive inbred Brown Norway (BN/Mcw) rats was introgressed into the background of Dahl salt-sensitive (SS/Mcw) rats. The present studies determined the mean arterial pressure (MAP) responses to salt; renal and peripheral vascular responses to norepinephrine (NE) and angiotensin II (AngII); and protein excretion and renal histology in rats that received a high salt (4% NaCl) for 3 weeks. Indwelling arterial catheters were implanted in the 2 nd week of high salt and MAP was recorded for 3 days during the 3 rd week of high salt, and again 36 hours after 10mg/kg Lasix and return to a low salt (0.4%) diet. Results: High salt MAP of SS/Mcw rats averaged 183+4 mmHg, SS BN13 averaged 124+3 mmHg, and BN/Mcw averaged 132+4 mmHg. The reduction in MAP with sodium depletion averaged 31.8+3 mmHg in SS/Mcw rats but was significantly less in SS BN13 rats (14.7+1.6 mmHg) and BN/Mcw rats (13.9+2 mmHg). Protein excretion of SS/Mcw rats on high salt averaged 270+31 mg/24hr compared to 55+22 mg/24hr in SS BN13 rats, and 19+7 mg/24hr in BN/Mcw rats. Reduction of renal blood flow to iv administration of NE and AngII, was significantly greater SS/Mcw rats compared to SS BN13 and BN/Mcw rats. Severe medullary interstitial fibrosis and tubular necrosis was consistently seen in SS/Mcw rat kidneys but not in the SS BN13 or BN/Mcw rats following 3 weeks of high salt intake. These results demonstrate the power of functional mapping of complex traits using chromosomal transfer techniques and reveal a powerful gene (or set of genes) within BN/Mcw chromosome 13 that confers protection from the detrimental effects of a high salt diet to the Dahl salt-sensitive rat (SS/Mcw). It remains to be determined if the renoprotective effect is secondary to the reduction in blood pressure with chromosomal transfer, or a direct protective effect.

Abstract 160: Characterization of a Comt Knock-out Rat for Blood Pressure and Associated Phenotypes.

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Marc Casati ◽  
Mathew Hoffman ◽  
Rebecca Schilling ◽  
Michael Flister ◽  
Aron M Geurts ◽  
...  
Keyword(s):  
Blood Pressure ◽  
High Salt ◽  
Male Rats ◽  
Zinc Finger Nucleases ◽  
Dependent Manner ◽  
Electrolyte Excretion ◽  
High Salt Diet ◽  
Salt Diet ◽  
Low Salt ◽  
Salt Sensitive Hypertension

The catecholamine system plays an important role in the control of blood pressure and sodium excretion. One of the inactivation pathways of catecholamines is the enzymatic metabolism by catechol-O-methyltransferase (Comt). There are conflicting data regarding the role of Comt on the development of salt-sensitive hypertension, so the goal of our study was to evaluate the importance of Comt in the context of a susceptible background in vivo. Comt was mutated in the Dahl SS rat by zinc finger nucleases (ZFNs) injections targeting the sequence CTGTTCCAGGTCACCATCctcaatGGGGCATCCCAGGATCTT into SS/JrHsdMcwi (Dahl S) rat embryos. The resulting mutation was a 14-bp frameshift deletion in exon 4. Conscious blood pressure was measured by telemetry on male and female Comt knockout and wild type (WT) rats on low salt diet (0.4% NaCl) and during three weeks of high salt diet (8%NaCl). Disruption of Comt caused the protein not to express in the kidneys of the Dahl S rat. There were no differences in mean arterial pressure (MAP) between the Comt -/- and the Comt +/+ male rats at any time point during the day-night cycle at low or high salt diet. Body and organ weights, and protein and electrolyte excretion was also unchanged by the Comt mutation. On the other hand, female Comt -/- rats evidenced a higher MAP, which was only significantly higher at night during low salt diet (112±2 mmHg in Comt +/+ vs 125±2 mmHg in the Comt -/-, n>6) and both during day and night after 21 days of high-salt diet (∼ 30 mmHg difference between Comt +/+ and Comt -/- strains at both day and night). Systolic blood pressure differences were mostly responsible for the observed blood pressure diferences in females KO of the Comt gene, despite blood pressure effect, was not followed by a parallel difference in urine flow, electrolyte excretion or renal damage (protein and albumin excretion). In conclusion, we are the first ones to show that disruption of Comt enhances salt-sensitive hypertension in a gender-dependent manner.

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