Congenic Rats For Hypertension: How Useful Are They For The Hunting Of Hypertension Genes?

Nabika, Toru; Kobayashi, Yuta; Yamori, Yukio

doi:10.1046/j.1440-1681.2000.03242.x

Cited by 25 publications

(31 citation statements)

References 49 publications

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“…16 Our analysis finds that this difference is sustained across the 3 SHR substrains examined. This gene has been thoroughly studied because of its differential expression, its position in a wellsubstantiated SHR BP QTL, [17][18][19][20][21] evidence of polymorphism in the Sa locus between SHR and WKY, 22,23 and evidence from human studies suggesting involvement in BP determination. 24 -26 Recent rat congenic studies have not found support for the involvement of Sa in BP regulation.…”

Section: Discussionmentioning

confidence: 99%

Combined Genealogical, Mapping, and Expression Approaches to Identify Spontaneously Hypertensive Rat Hypertension Candidate Genes

et al. 2005

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Abstract-Allelic expression in genes has become recognized as a heritable trait by which phenotypes are generated. We have examined gene expression in the rat kidney using genome-wide microarray technology (Affymetrix). Gene expression was determined across 4 rat strains, 3 hypertensive spontaneously hypertensive rat (SHR) substrains (SHR-A3, SHR-B2, and SHR-C), and a normotensive strain (Wistar-Kyoto [WKY]). Expression measurements were made in multiple animals from all strains at 4 time points (4 weeks, 8 weeks, 12 weeks, and 18 weeks of age), covering the prehypertensive period in SHR (4 weeks), and the period of rapidly rising blood pressure (8 and 12 weeks) and of sustained hypertension (18 weeks). Regression analysis revealed a close relationship across all strains during the first 3 time points, after which SHR-A3 became a substantial outlier. SHR-B2 and SHR-C demonstrated a very close relationship in gene expression at all times but also showed increased differences compared with the other strains at 18 weeks of age. We identified genes that were consistently different in expression, comparing all SHR substrains at each time point with WKY. The resulting list of genes was compared with blood pressure quantitative trait loci reported for SHR to refine a number of genes consistently differentially expressed between SHR substrains and WKY, persistently differentially expressed across multiple time points, and located in SHR blood pressure-determinative regions of the genome. Genealogical relationships and SHR substrain intercrosses suggest that genes responsible for heritable hypertension in SHR are shared across SHR substrains.

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Section: Discussionmentioning

confidence: 99%

Combined Genealogical, Mapping, and Expression Approaches to Identify Spontaneously Hypertensive Rat Hypertension Candidate Genes

et al. 2005

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“…Overnight urine samples were collected from groups of 4-5 adult mice in flasks containing tri phenylphosphine (2-3 mg each) (30). After adding synthetic [20 2 H3]-labeled 8,9; 11,12; and 14,15EET (5 ng each) and [5,6,8,9,11,12, and 14,15 2 H8]-labeled 8,9; 11,12; and 14,15DHET (5 ng each) as internal standards, the urine EETs and DHETs were extracted with acidified CHCl3/CH3OH (2:1) (24), purified by reverse phase HPLC as described (24), and methylated by reaction with diazomethane in ethyl ether (24). The resulting methylEETs and methylDHETs were quantified by LC/MS/MS using an Agilent Eclipse XDBC8 column (2.1 × 150 mm; 5 mm) connected to a TSQQuantum MS/MS spectrometer (Thermo Electron Corp.).…”

Section: Methodsmentioning

confidence: 99%

“…Earlier studies identified members of the P450 CYP2C and CYP4A gene sub families as functionally relevant AA epoxygenases and ωhydroxy lases, respectively (8)(9)(10)(11), and implicated them in the control of renal function and blood pressure (9)(10)(11). However, the unequivocal inter pretation of these studies is complicated by the in vitro nature of the functional data available (8)(9)(10)(11) and genetic complexity of the animal models studied (9)(10)(11)(12)(13). Consequently, notwithstanding their poten tial clinical importance, the physiological role of these enzymes in blood pressure regulation remains ambiguous and in need of experi mental confirmation.…”

Section: Introductionmentioning

confidence: 99%

Salt-sensitive hypertension is associated with dysfunctional Cyp4a10 gene and kidney epithelial sodium channel

Nakagawa

Holla

Wei

et al. 2006

Journal of Clinical Investigation

131

206

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Functional and biochemical data have suggested a role for the cytochrome P450 arachidonate monooxygenases in the pathophysiology of hypertension, a leading cause of cardiovascular, cerebral, and renal morbidity and mortality. We show here that disruption of the murine cytochrome P450, family 4, subfamily a, polypeptide 10 (Cyp4a10) gene causes a type of hypertension that is, like most human hypertension, dietary salt sensitive. Cyp4a10 -/-mice fed low-salt diets were normotensive but became hypertensive when fed normal or high-salt diets. Hypertensive Cyp4a10 -/-mice had a dysfunctional kidney epithelial sodium channel and became normotensive when administered amiloride, a selective inhibitor of this sodium channel. These studies (a) establish a physiological role for the arachidonate monooxygenases in renal sodium reabsorption and blood pressure regulation, (b) demonstrate that a dysfunctional Cyp4a10 gene causes alterations in the gating activity of the kidney epithelial sodium channel, and (c) identify a conceptually novel approach for studies of the molecular basis of human hypertension. It is expected that these results could lead to new strategies for the early diagnosis and clinical management of this devastating disease. IntroductionPrevalence, complexity, and multiple medical and socioeconomic consequences make hypertension a major health challenge for most of the Western world (1). While environmental factors and coexist ing conditions play a role in the development and progression of hypertension, segregation and linkage analyses indicate that mul tiple genetic factors contribute to its complex etiology (2-7). Fur thermore, clinical studies show that the cardiovascular and renal morbidity and mortality resulting from hypertension are markedly reduced by timely diagnosis and early clinical intervention (1). As the kidneys play a central role in the control of body salt and fluid balance, they are frequent targets for the treatment of hypertension, especially those forms sensitive to dietary salt (2-5). However, since the molecular basis of prevalent forms of the disease remains uncer tain, its early diagnosis and treatment are largely symptomatic. It is expected that the identification of novel pathways/genes involved in blood pressure variations (3, 6, 7) will lead to new therapeutic targets and to improved diagnosis and prevention. Indeed, early detection and treatment are urgently needed to prevent the dangerous and profound consequences of untreated chronic hypertension.The metabolism of endogenous arachidonic acid (AA) to epoxy eicosatrienoic acids (EETs) and 20hydroxyeicosatetraenoic acid

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“…The WKY-based congenic strain, WKY.SHRSP-(D1Wox29-D1Arb21)/Izm (abbreviated as WKYpch1.0 hereafter), was established by the transfer of the chromosomal segment between D1Wox29 and D1Arb21 from SHRSP onto the genetic background of WKY as previously described (10). The SHRSP-based congenic rat, SHRSP.WKY-(D1Wox29-D1Arb21)/Izm (abbreviated as SHRSPwch1.0), was designed to possess the genomic composition corresponding to that of the WKYpch1.0 (11).…”

Section: Animalsmentioning

confidence: 99%

Sympathetic Regulation of the Renal Functions in Rats Reciprocally Congenic for Chromosome 1 Blood Pressure Quantitative Trait Locus

et al. 2008

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Congenic Rats For Hypertension: How Useful Are They For The Hunting Of Hypertension Genes?

Cited by 25 publications

References 49 publications

Combined Genealogical, Mapping, and Expression Approaches to Identify Spontaneously Hypertensive Rat Hypertension Candidate Genes

Combined Genealogical, Mapping, and Expression Approaches to Identify Spontaneously Hypertensive Rat Hypertension Candidate Genes

Salt-sensitive hypertension is associated with dysfunctional Cyp4a10 gene and kidney epithelial sodium channel

Sympathetic Regulation of the Renal Functions in Rats Reciprocally Congenic for Chromosome 1 Blood Pressure Quantitative Trait Locus

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