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  • Ovid Technologies (Wolters Kluwer Health)  (16)
  • 2010-2014  (16)
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  • Ovid Technologies (Wolters Kluwer Health)  (16)
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  • 2010-2014  (16)
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  • 1
    Online Resource
    Online Resource
    Abstract 55: Involvement of Matrix Metalloproteinase-2 During the Progression of Renal Disease in Diabetic Dahl Salt-sensitive Rats
    Ovid Technologies (Wolters Kluwer Health) ; 2012
    In:  Hypertension Vol. 60, No. suppl_1 ( 2012-09)
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 60, No. suppl_1 ( 2012-09)
    Abstract: Recently, our laboratory reported that Dahl salt-sensitive (SS) rats develop a form of renal disease following induction of diabetes with streptozotocin (STZ) that is similar to patients with diabetic nephropathy (DN). The progression of renal injury in this model was associated with increased levels of matrix metalloproteinase-2 (MMP-2) in the renal cortex. The present study examined the role of MMP-2 during the progression of diabetes-induced renal injury by comparing the development of proteinuria and renal injury following the induction of type I diabetes in SS rats and in a MMP-2 Zinc finger KO strain of SS rats with an 8 base pair frame-shift deletion (1433-1440) in exon 7 (MMP-2 ZN KO strain). The glomerular expression of MMP-2 protein was non-detectable in the MMP-2 ZN KO strain compared to SS rats fed a low salt (LS) diet. We next performed studies using 9 week-old SS and MMP-2 ZN KO rats treated with either vehicle or (2) STZ, 50 mg/kg (i.p.) to induce diabetes and fed the rats a low salt (LS) diet containing 0.4% NaCl to minimize the development of hypertension. At 18 weeks of age, protein excretion increased to 303±39 mg/day in STZ-treated SS rats (n=7) versus 112±12 mg/day in vehicle treated rats. Protein excretion only increased to 150±23 mg/day in the STZ-treated MMP-2 ZN KO strain (n=7). Blood pressure was not significantly altered and averaged 109±4 mmHg in vehicle and STZ-treated SS rats versus 108±4 mmHg in the STZ-treated MMP2-ZN KO animals. STZ-treated SS rats exhibited marked glomerular injury and extensive renal fibrosis. The degree of glomerulosclerosis and renal interstitial fibrosis was significantly reduced in the kidneys of the MMP-2 ZN KO strain. These data indicate that the progression of diabetes-induced renal injury in STZ-SS rats is associated with upregulation of the expression and activity of MMP-2 and that KO of MMP-2 gene function markedly reduces the development of proteinuria and renal injury in this model of type I diabetic nephropathy. These results also suggest that selective MMP inhibitors may be useful to prevent the development and/or progression of chronic kidney disease in the millions of patients suffering from diabetes.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/hyp.60.suppl_1.A55
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2012
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  • 2
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    Abstract 480: NaCl-Independent Dietary Effects are Associated with Altered DNA Methylation in Dahl Salt-Sensitive (SS) Hypertension
    Ovid Technologies (Wolters Kluwer Health) ; 2013
    In:  Hypertension Vol. 62, No. suppl_1 ( 2013-09)
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 62, No. suppl_1 ( 2013-09)
    Abstract: Salt-sensitive hypertension and renal damage were compared in colonies of SS rats fed casein-and grain-based diets. When 6 week old rats were fed a low NaCl diet (n=7-11/group), mean arterial pressure (MAP) and urinary albumin (UAlb) excretion were not significantly different in grain-fed rats compared to values in casein-fed rats (107±2 mmHg and 6±2 mg/day). Increasing dietary NaCl intake to 4.0% for three weeks led to a significantly greater increase in MAP (171±7 vs 119±7 mmHg), UAlb (164±19 vs 24±6 mg/day) and renal histological damage in SS rats fed the casein diet (p 〈 .05). To assess mechanisms of this NaCl independent effect, an RNA-Seq analysis of renal outer medullary tissue of rats (n=4/group) fed the grain- or casein-based diets was performed. Over 1500 known genes were differentially expressed between the casein- and grain-fed rats on low salt; over 2100 were different between the groups fed the 4.0% chow (FDR 〈 0.05); and 897 genes were common to these two data sets. The differentially expressed genes were significantly enriched for genes related to hematopoietic cell lineage, the complement and coagulation cascade, B-cell signaling, NK cell-mediated cytotoxicity, and primary immunodeficiency. To understand potential mechanisms of the regulation of gene expression, a genome-wide DNA methylation analysis of the renal outer medulla at single-base resolution was performed. Of nearly 3,000 methylated CpG islands identified, 534 and 650 were differentially methylated between the casein and grain fed groups when comparing effects of low to high salt diets, respectively (FDR 〈 0.05). Approximately 200 differentially methylated CpG islands were located in the proximity of transcriptional start sites. We first focused our attention on several genes which exhibited a reciprocal pattern of DNA methylation and RNA abundance. These include Klotho (an aging-related gene), and Cyp39a1 (a cytochrome P450) which exhibited significantly more 5-methylcytosine modifications in the transcription start site and reduced mRNA expression in rats fed the casein-based diet with low salt. These data provide evidence that epigenetic modifications due to NaCl-independent dietary effects may alter salt-sensitive blood pressure and renal disease phenotypes.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/hyp.62.suppl_1.A480
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
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  • 3
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    HV1 Acts as a Sodium Sensor and Promotes Superoxide Production in Medullary Thick Ascending Limb of Dahl Salt-Sensitive Rats
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Hypertension Vol. 64, No. 3 ( 2014-09), p. 541-550
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 64, No. 3 ( 2014-09), p. 541-550
    Abstract: We previously characterized a H + transport pathway in medullary thick ascending limb nephron segments that when activated stimulated the production of superoxide by nicotinamide adenine dinucleotide phosphate oxidase. Importantly, the activity of this pathway was greater in Dahl salt-sensitive rats than salt-resistant (SS.13 BN ) rats, and superoxide production was enhanced in low Na + media. The goal of this study was to determine the molecular identity of this pathway and its relationship to Na + . We hypothesized that the voltage-gated proton channel, HV1, was the source of superoxide-stimulating H + currents. To test this hypothesis, we developed HV1 −/− null mutant rats on the Dahl salt-sensitive rat genetic background using zinc-finger nuclease gene targeting. HV1 could be detected in medullary thick limb from wild-type rats. Intracellular acidification using an NH 4 Cl prepulse in 0 sodium/BaCl 2 containing media resulted in superoxide production in thick limb from wild-type but not HV1 −/− rats ( P 〈 0.05) and more rapid recovery of intracellular pH in wild-type rats (ΔpH I 0.005 versus 0.002 U/s, P =0.046, respectively). Superoxide production was enhanced by low intracellular sodium ( 〈 10 mmol/L) in both thick limb and peritoneal macrophages only when HV1 was present. When fed a high-salt diet, blood pressure, outer medullary renal injury (tubular casts), and oxidative stress (4-hydroxynonenal staining) were significantly reduced in HV1 −/− rats compared with wild-type Dahl salt-sensitive rats. We conclude that HV1 is expressed in medullary thick ascending limb and promotes superoxide production in this segment when intracellular Na + is low. HV1 contributes to the development of hypertension and renal disease in Dahl salt-sensitive rats.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/HYPERTENSIONAHA.114.03549
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
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  • 4
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    Abstract 39: Cyp4a1 Transgenic Rats Generated Using Sleeping Beauty Transposon System Restores the Impaired Myogenic Responses in the Afferent Arteriole of Dahl S Rats
    Ovid Technologies (Wolters Kluwer Health) ; 2013
    In:  Hypertension Vol. 62, No. suppl_1 ( 2013-09)
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 62, No. suppl_1 ( 2013-09)
    Abstract: We have reported that the production of 20-HETE is reduced in the renal vasculature of Dahl S rats and that myogenic and TGF responses of afferent arteries (Af-Art) are impaired in Dahl S rats. In this study we generated CYP4A1 transgenic rats in the Dahl S inbred strain background utilizing the enhanced Sleeping Beauty (SB100X) transposon system to determine if upregulation of 20-HETE production can restore vascular reactivity and oppose the development of renal injury. Fertilized eggs collected from female Dahl S rats were microinjected with a transposon vector harboring the rat CYP4A1 cDNA under the control of the ubiquitous CAG promoter along with SB100X transposase mRNA to produce transgenic founders. Heterozygous founders were backcrossed to Dahl S rats, transgene insertion sites were identified by Ligation Mediated PCR and sequencing, and the progeny were brother-sister mated to derive homozygous transgenic lines. The expression of CYP4A protein was significantly elevated and the production of 20-HETE was 3-fold higher in the renal outer medullary tissue of CYP4A1 transgenic (n=17) compared to Dahl S rats (n=17). 20-HETE production was 10-fold higher in renal microvessels of CYP4A1 transgenic animals than Dahl S rats. (0.2±0.3, n=22 versus 1.9±0.1 pmol/mg/min, n=14). The luminal diameter of the Af-Art decreased significantly from 15.9 ± 0.6 to 14.1 ± 0.5 μm in CYP4A1 transgenic rats (n=5) when the perfusion pressure was increased from 60 to 120 mmHg, whereas it remained unaltered in Dahl S rats (from 19.4 ± 2.3 to 20.6 ± 5.6 μm, n=22). These studies further support the view that a deficiency in the formation of 20-HETE in the renal microcirculation contributes to the marked susceptibility of Dahl S rats to develop of hypertension and diabetic induced renal injury, and the new CYP4A1 transposon transgenic rat model may be useful for determining the mechanisms involved.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/hyp.62.suppl_1.A39
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
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  • 5
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    Abstract 353: Rapid Gene Editing in Rat Models of Human Disease Using Targeted Nucleases
    Ovid Technologies (Wolters Kluwer Health) ; 2012
    In:  Hypertension Vol. 60, No. suppl_1 ( 2012-09)
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 60, No. suppl_1 ( 2012-09)
    Abstract: Previous investigations into mechanisms of genes in animal models have primarily used the mouse because of the availability of technologies for targeted manipulation of its genome in embryonic stem (ES) cells. To accelerate functional mechanistic studies in other species where ES technology is not yet widespread, we recently developed an alternative and rapid method for generating targeted mutations in rat genes by the application of Zinc Finger Nucleases (ZFNs). When introduced into an embryo, ZFNs target and induce a chromosome double strand DNA break at the investigator-specified locus, stimulating cellular responses which can result in knock out or knock in modifications at the locus. Using commercially available reagents, we targeted and disrupted more than 100 protein-coding genes across 13 different inbred, consomic, and outbred genetic backgrounds with a 97% (102/105) success rate in approximately 30 months. ZFNs can therefore access nearly every gene in the rat genome and can induce multiple different alleles at the target locus. The majority of mutations, 81% (355/437) were simple deletions ranging from 1-228 base pairs (median 13-bp) and upon breeding, 94% (178/189) of mutations were transmitted to the next generation with little evidence of germline mosaicism. Many of these strains are now available for functional mechanistic studies of candidate human disease genes for hypertension and chronic kidney disease. Co-introduction of a homologous gene template with the ZFNs could stimulate knockin at three different loci in the rat genome. Gene knock into the rat Rosa26 locus allows for uniform expression of a gene in all cells and tissues of the adult animal as well as germline-competent ES cells derived from the Fawn Hooded Hypertensive strain. This knockin technology in embryos and ES cells offers many new opportunities to make very precise modifications to the rat genome and is a key step toward creating conditional gene alleles in the rat. Transcriptional activator-like effector nucleases (TALENs) are also active in the rat embryo and we have disrupted 70% (7/10) genes with this new technology. In sum, targeted nuclease technology is enabling many new genetic approaches to the rat and other model systems to create even better human disease models.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/hyp.60.suppl_1.A353
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2012
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  • 6
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    Abstract 78: Protective Effect of Nox4 in Salt-induced Hypertension in Dahl Salt-induced Rats
    Ovid Technologies (Wolters Kluwer Health) ; 2013
    In:  Hypertension Vol. 62, No. suppl_1 ( 2013-09)
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 62, No. suppl_1 ( 2013-09)
    Abstract: It is recognized that oxidative stress plays a critical role in the development of salt-sensitive hypertension, especially in the kidney. The most abundant renal isoform is Nox4, but there is controversy regarding its distribution and function. There have been no studies of the role of Nox4 in a naturally occurring form of hypertension (Dahl salt-sensitive (SS) rat). We have therefore knocked out the Nox4 gene in the SS genetic background (SS Nox4-/- ) to determine the effect upon the development of salt-sensitive hypertension and renal kidney injury in the SS rat. The SS Nox4-/- rat, developed using zinc finger nuclease (ZFN) techniques, exhibits an 8 base-pair frame-shift deletion within exon 7 resulting in a truncation of the Nox4 peptide by 195 amino acids with a molecular weight of 22 kD predicted (compared to the full length Nox4 peptide of 594 amino acids with a molecular weight of 68 kD). Western blot analysis confirmed the loss of the Nox4 band at ~65 kD in renal medullary tissue of SS Nox4-/- rats vs. SS. The functional consequence of this deletion was substantial over a 21 day period following an increase in salt intake from 0.4 (LS) to 4.0% NaCl (HS). SS Nox4-/- rats exhibited a change in MAP from 105±3 on LS to 130±2 mmHg (a change of 25 mmHg; n=10) on d21 of HS compared to a change from 107±2 mmHg in SS rats to 171±7 on d21 of HS (a change of 64 mmHg; n=10) as determined by telemetry. Albuminuria was virtually eliminated in SS Nox4-/- rats who also exhibited a large reduction of tubular cast (2.4±0.3% positive strained region vs 12.6±1.3 in SS). Glomerular injury in both the cortex and medulla was significantly less in the SS Nox4-/- than the SS. The % of glomeruli with an injury score of 〉 2 (0-4 scale) was 43±1.5% (258 of 600 glomeruli) in the SS Nox4-/- but 65±3.9% (390 of 600) in the SS. We conclude that Nox4 plays an important role in the development of this form of salt-sensitive hypertension and renal injury in SS rats.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/hyp.62.suppl_1.A78
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
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  • 7
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    Abstract 222: Upregulation Of Cyp4a1 Gene Expression Restores The Impaired Myogenic Response And Autoregulation Of Cerebral Blood Flow In Dahl Salt Sensitive Rats
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Hypertension Vol. 64, No. suppl_1 ( 2014-09)
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 64, No. suppl_1 ( 2014-09)
    Abstract: We have reported that a reduction in the expression of CYP4A and the production of 20-HETE in the renal outer medulla contributes to development of hypertension in Dahl salt sensitive (SS) rats. The present study examined whether 20-HETE production is also reduced in the vasculature and if a deficiency in the formation of 20-HETE in the vasculature alters vascular tone and promotes end organ damage. The production of 20-HETE, the myogenic response of middle cerebral arteries (MCA) and autoregulation of cerebral blow flow (CBF) was compared in SS, CYP4A1 transgenic SS rats and SS.5BN consomic rats in which chromosome 5 from Brown Norway (BN) was transferred into the SS genetic background. 20-HETE production was 6-fold higher in cerebral arteries obtained from CYP4A1 transgenic (n=25) and SS.5BN (n=4)rats than in SS (n=17) rats 0.77 ± 0.08 versus 0.12 ± 0.03 pmol/mg/min). The luminal diameter of MCA decreased to 70 ± 3 % in CYP4A1 transgenic rats and to 65 ± 6 in SS.5BN when perfusion pressure was increased from 40 to 140 mmHg, whereas it remained unaltered in SS rats. Administration of the inhibitor of the synthesis of 20-HETE, HET0016 (10 uM), abolished the myogenic response in MCA of CYP4A1 transgenic and SS.5BN rats but had no effect in SS rats. CBF was poorly autoregulated and increased by 49 ± 6% in SS rats as MAP was increased by 60% from 100 to 160 mmHg. In contrast, CBF was only increased by 26 ± 5% and in SS.5BN rats and by 19 ± 2% in CYP4A1 transgenic rats when MAP was increased in the same range. These results indicate that a genetic deficiency of 20-HETE contributes to an impaired myogenic response in autoregulation of CBF in SS rats which may contribute to vascular remodeling, stroke and dementia following the onset of hypertension.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/hyp.64.suppl_1.222
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
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  • 8
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    Exacerbated Pulmonary Arterial Hypertension and Right Ventricular Hypertrophy in Animals With Loss of Function of Extracellular Superoxide Dismutase
    Ovid Technologies (Wolters Kluwer Health) ; 2011
    In:  Hypertension Vol. 58, No. 2 ( 2011-08), p. 303-309
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 58, No. 2 ( 2011-08), p. 303-309
    Abstract: Studies have demonstrated that increased oxidative stress contributes to the pathogenesis and the development of pulmonary artery hypertension (PAH). Extracellular superoxide dismutase (SOD3) is essential for removing extracellular superoxide anions, and it is highly expressed in lung tissue. However, it is not clear whether endogenous SOD3 can influence the development of PAH. Here we examined the effect of SOD3 knockout on hypoxia-induced PAH in mice and a loss-of-function SOD3 gene mutation (SOD3 E124D ) on monocrotaline (40 mg/kg)-induced PAH in rats. SOD3 knockout significantly exacerbated 2 weeks of hypoxia-induced right ventricular (RV) pressure and RV hypertrophy, whereas RV pressure in SOD3 knockout mice under normoxic conditions is similar to wild-type controls. In untreated control rats at age of 8 weeks, there was no significant difference between wild-type and SOD3 E124D rats in RV pressure and the ratio of RV weight:left ventricular weight (0.25±0.02 in wild-type rats versus 0.25±0.01 in SOD3 E124D rats). However, monocrotaline caused significantly greater increases of RV pressure in SOD3 E124D rats (48.6±1.8 mm Hg in wild-type versus 57.5±3.1 mm Hg in SOD3 E124D rats), of the ratio of RV weight:left ventricular weight (0.41±0.01 versus 0.50±0.09; P 〈 0.05), and of the percentage of fully muscularized small arterioles in SOD3 E124D rats (55.2±2.3% versus 69.9±2.6%; P 〈 0.05). Together, these findings indicate that the endogenous SOD3 has no role in the development of PAH under control conditions but plays an important role in protecting the lung from the development of PAH under stress conditions.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/HYPERTENSIONAHA.110.166819
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2011
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  • 9
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    Abstract 154: GWAS Candidate Gene Knockout in Rats Reveals a Role for Erk/mapk Signaling in Hypertension
    Ovid Technologies (Wolters Kluwer Health) ; 2012
    In:  Hypertension Vol. 60, No. suppl_1 ( 2012-09)
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 60, No. suppl_1 ( 2012-09)
    Abstract: The data revealed by GWAS studies provide a wealth of candidate human disease genes now requiring functional validation in animal models. In two years, we disrupted a large set of GWAS candidate genes for human hypertension and chronic kidney disease by Zinc Finger Nuclease (ZFN)-mediated gene targeting in the SS (Dahl salt-sensitive) strain background. Phenotyping male rats from gene-disrupted strains revealed five genes ( Sh2b3 , Rasgrp3 , Gpr73 , Ulk3 , and Wdr72 ) significantly altering the salt-induced hypertension in and renal damage phenotypes in this model strain of human hypertension compared to age matched wild type controls. Ingenuity Pathway Analysis revealed a putative connection for four of these genes ( Sh2b3 , Rasgrp3 , Gpr73 , and Ulk3 ) to the ERK/MAPK signaling pathway and suggested that decreased ERK signaling would exacerbate disease in the SS model. To test this hypothesis, we measured the response of SS rats to a 4% salt diet with daily IP injections of the MEK inhibitor PD98059 or vehicle control. Wild type SS animals treated with PD98059 show a significant increase in mean arterial pressure compared to vehicle-injected controls (n=10, 142±7 vs. 126±6 mmHg respectively, P 〈 0.05) suggesting that ERK signaling plays an important role in the pathogenesis of this model. In conclusion, we have used gene knockout in a hypertensive rat model to identify genes and associated pathway mechanisms of BP regulation. The gene disruption phenotype and participation of multiple genes in the ERK/MAPK signaling pathway indicates that regulation of this pathway plays a major role in determining blood pressure.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/hyp.60.suppl_1.A154
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2012
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  • 10
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    Abstract 50: Characterization of the Gwas-nominated Agtrap-plod1 Locus Using Zfn-mutated Rats
    Ovid Technologies (Wolters Kluwer Health) ; 2012
    In:  Hypertension Vol. 60, No. suppl_1 ( 2012-09)
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 60, No. suppl_1 ( 2012-09)
    Abstract: Background: Genome-wide association studies (GWAS) are frequently used to nominate candidate genes for complex diseases, but are largely unable to identify the causative variant(s). One example: the AGTRAP-PLOD1 locus contains 6 genes in close proximity that are all associated with blood pressure (BP), making it difficult to delineate specific allele(s) that underlie human hypertension at this locus. Here we present a novel rat model that was developed to rapidly dissect GWAS loci using high-throughput gene mutation on a single hypertensive background. METHODS: Agtrap, Mthfr, Clcn6, Nppa, Nppb, and Plod1 were individually mutated in the Dahl SS rat by zinc finger nuclease (ZFN) injections. ZFN-mutated and wild type (WT) control SS rats (n=8-25 per group) were assessed for BP and renal damage after 10 days on a 4% NaCl diet. Temporal gene expression during development of hypertension was assessed by qRT-PCR and confirmed by RNA-seq. Results: Expression of all AGTRAP-PLOD1 transcripts changed significantly in response to elevated BP, indicating possible roles of the entire AGTRAP-PLOD1 locus in salt-sensitive hypertension. However, compared with WT, only NPPA mutation further increased mean BP (Δ+27mmHg, P 〈 0.001) and heart weight (1.62±0.03 vs. 1.13±0.03g, P 〈 0.001) in response to 4% NaCl diet. In contrast, CLCN6 mutation significantly decreased diastolic BP (Δ-22mmHg, P 〈 0.001) but had no effect on systolic BP compared to WT. Following salt challenge, proteinuria was elevated by mutation of PLOD1 (147±12 mg/day, P 〈 0.001) and MTHFR (132±23 mg/day, P 〈 0.05) compared with WT littermates (91±5 mg/day), whereas AGTRAP mutation decreased protein excretion (54±9 mg/day, P 〈 0.05). Analysis of haplotype blocks that are associated with gene expression and human hypertension confirmed that NPPA, CLCN6, and MTHFR are the primary mediators of BP changes linked to the AGTRAP-PLOD1 locus. Conclusions: Combined with human GWAS, our data show for the first time that NPPA and CLCN6 are divergent mediators of BP at the AGTRAP-PLOD1 locus, while MTHFR mutation directly increases susceptibility to end-stage renal disease. These novel mechanistic data provide rationale for developing haplotype-specific therapies for treating hypertension.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/hyp.60.suppl_1.A50
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2012
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