A genetic model of malignant phase hypertension in rats

Whitworth, Caroline; Fleming, Stewart; Kotelevtsev, Yuri; Manson, Lynn; Brooker, Gillian; Cumming, Allan D.; Mullins, John J.

doi:10.1038/ki.1995.66

Cited by 37 publications

(38 citation statements)

References 29 publications

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“…Thus, the severe phenotype induced by the high dose of I3C is characteristic of malignant hypertension. 9,23,[31][32][33][34] Dietary administration of high-dose I3C did not alter either systolic blood pressure (144±5 vs. 147±6 mmHg) or body weight 307±10 vs. 322±6 g) of transgene-negative rats, indicating that the I3C-induced hypertension and weight loss were not the result of non-specific effects of I3C. Indeed, chronic administration of the AT 1 -receptor antagonist, candesartan, prevented the development of hypertension and loss of body weight in Cyp1a1-Ren2 transgenic rats induced with high-dose I3C.…”

Section: Resultsmentioning

confidence: 99%

“…[18][19][20][21]24,26 In contrast, administration of the higher dose (0.3%) of I3C induced a more rapidly developing hypertension that was associated with the clinical manifestations of malignant hypertension including pronounced weight loss, lethargy, hunched posture and polyuria. 9,23,[31][32][33][34][35] This difference in the phenotype produced by the two doses of I3C occurred despite exposure to similar levels of BP after 5-6 days of transgene induction. The present observation that dietary I3C did not alter BP or body weight in nontransgenic rats indicates that the effects of I3C on BP were not the result of non-specific effects of I3C, but were due specifically to activation of the Cyp1a1-Ren2 transgene.…”

Section: Discussionmentioning

confidence: 99%

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Genetic Clamping of Renin Gene Expression Induces Hypertension and Elevation of Intrarenal Ang II Levels of Graded Severity in Cyp1a1-Ren2 Transgenic Rats

Mitchell

Bagatell

Miller

et al. 2006

J Renin Angiotensin Aldosterone Syst

153

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Introduction. Transgenic rats with inducible angiotensin II (Ang II)-dependent hypertension (strain name: TGR[Cyp1a1-Ren2]) were generated by inserting the mouse Ren2 renin gene, fused to the cytochrome P450 1a1 (Cyp1a1) promoter, into the genome of the rat. The present study was performed to characterise the changes in plasma and kidney tissue Ang II levels and in renal haemodynamic function in Cyp1a1-Ren2 rats following induction of either slowly developing or malignant hypertension in these transgenic rats. Materials and Methods. Arterial blood pressure (BP) and renal haemodynamics and excretory function were measured in pentobarbital sodium-anaesthetised Cyp1a1-Ren2 rats fed a normal diet containing either a low dose (0.15%, w/w for 14-15 days) or high dose (0.3%, w/w for 11-12 days) of the aryl hydrocarbon indole-3-carbinol (I3C) to induce slowly developing and malignant hypertension, respectively. In parallel experiments, arterial blood samples and kidneys were harvested for measurement of Ang II levels by radioimmunoassay. Results. Dietary I3C increased plasma renin activity (PRA), plasma Ang II levels, and arterial BP in a dose-dependent manner. Induction of different fixed levels of renin gene expression and PRA produced hypertensive phenotypes of varying severity with rats developing either mild or malignant forms of hypertensive disease. Administration of I3C, at a dose of 0.15% (w/w), induced a slowly developing form of hypertension whereas administration of a higher dose (0.3%) induced a more rapidly developing hypertension and the clinical manifestations of malignant hypertension including severe weight loss. Both hypertensive phenotypes were characterised by reduced renal plasma flow, increased filtration fraction, elevated PRA, and increased plasma and intrarenal Ang II levels. These I3C-induced changes in renal haemodynamics, PRA and kidney Ang II levels were more pronounced in Cyp1a1-Ren2 rats with malignant hypertension. Chronic administration of the AT 1 -receptor antagonist,

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genetic Clamping of Renin Gene Expression Induces Hypertension and Elevation of Intrarenal Ang II Levels of Graded Severity in Cyp1a1-Ren2 Transgenic Rats

Mitchell

Bagatell

Miller

et al. 2006

J Renin Angiotensin Aldosterone Syst

153

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“…Organs were removed and fixed in 10% formal saline for 24 h and processed to paraffin block, and 4-m sections were cut and stained using hematoxylin and eosin (H&E), periodic acid-Schiff, and Martius Scarlet Blue (MSB) as reported previously (24).…”

Section: Pathologymentioning

confidence: 99%

Controlled Hypertension, a Transgenic Toggle Switch Reveals Differential Mechanisms Underlying Vascular Disease

Kantachuvesiri¹,

Fleming²,

Peters³

et al. 2001

Journal of Biological Chemistry

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141

297

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A novel inbred rat model with inducible hypertension has been generated using a renin transgene under the transcriptional control of the cytochrome P450, Cyp1a1 promoter. The degree and duration of hypertension are regulated tightly by administration of the natural xenobiotic indole-3 carbinol and can be readily reversed. Induction experiments reveal distinct temporal and mechanistic responses to hypertensive injury in different vascular beds, which is indicative of differential susceptibility of organs to a hypertensive stimulus. The mesentery and heart exhibited the greatest sensitivity to damage, and the kidney showed an adaptive response prior to the development of malignant hypertensive injury. Quantitative analysis of morphological changes induced in mesenteric resistance arteries suggest eutrophic remodeling of the vessels. Kinetic evidence suggests that locally activated plasma prorenin may play a critical role in mediating vascular injury. This model will facilitate studies of the cellular and genetic mechanisms underlying vascular injury and repair and provide a basis for the identification of novel therapeutic targets for vascular disease.Essential hypertension has a complex multifactorial phenotype. Both genetic and environmental factors influence its development, and understanding the pathogenesis of complications such as vascular lesions and end-organ damage may lead to more specific treatment and targeted intervention.We have identified candidate loci in rats that may contribute to target organ damage and mortality in malignant hypertension (MH), 1 a condition characterized by an accelerated rise in blood pressure, endothelial injury, activation of the reninangiotensin system, and microangiopathy (1). Several animal models have been generated to investigate the pathophysiology of hypertensive vascular injury. Most animal models of MH to date require surgical or pharmacological intervention to precipitate onset or depend on the constitutive expression of endogenous genes or heterologous transgenes (2-5). In rats doubly transgenic for human renin and angiotensinogen genes, hypertension and fibrinoid vasculitis (5) accompanied by alteration in surface adhesion molecules, proinflammatory cytokines, fibrogenic mediators and leukocyte infiltration (6) have been reported. In most of these models, the onset of disease cannot be determined precisely.The initiation events of pathological processes can only be studied in an animal model in which hypertension is induced by tightly temporally regulated gene expression. If the onset and level of hypertension can be controlled, then the cellular and molecular events during initiation of the vascular and organ injury can be identified unequivocally. Reversibility of the gene expression provides an opportunity to study the molecular and cellular basis of repair. We therefore have generated inbred transgenic rats with inducible hypertension using the cytochrome P450 promoter, Cyp1a1, to drive expression of the mouse Ren-2 gene. The transgene is expressed primarily ...

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“…Malignant hypertension is a severe form of hypertension characterized by rapidly increasing blood pressure, pressure diuresis and natriuresis, severe renal vasoconstriction and ischemia, activation of the renin-angiotensin system, microangiopathy, hemolytic anemia, and development of retinopathy (23,47,48). The vascular lesions of malignant hypertension in the kidney include myointimal proliferation and fibrinoid necrosis…”

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confidence: 99%

Renal vascular and tubulointerstitial inflammation and proliferation in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension

Graciano

Mouton²,

Patterson³

et al. 2007

American Journal of Physiology-Renal Physiology

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Graciano ML, Mouton CR, Patterson ME, Seth DM, Mullins JJ, Mitchell KD. Renal vascular and tubulointerstitial inflammation and proliferation in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension. Am J Physiol Renal Physiol 292: F1858 -F1866, 2007. First published March 6, 2007;doi:10.1152/ajprenal.00469.2006.-Transgenic rats with inducible ANG II-dependent malignant hypertension [TGR(Cyp1a1Ren2)] were generated by inserting the mouse Ren2 renin gene into the genome of the rat. The present study was performed to assess renal morphological changes occurring during the development of ANG IIdependent malignant hypertension in these rats. Male Cyp1a1-Ren2 rats (n ϭ 10) were fed normal rat food containing indole-3-carbinol (I3C; 0.3%) for 10 days to induce malignant hypertension. Rats induced with I3C had higher mean arterial pressures (173 Ϯ 9 vs. 112 Ϯ 11 mmHg, P Ͻ 0.01) than noninduced normotensive rats (n ϭ 9). Glomerular damage was evaluated by determination of the glomerulosclerosis index (GSI) in tissue sections stained with periodic acid-Schiff. Kidneys of hypertensive rats had a higher GSI than normotensive rats (21.3 Ϯ 5.6 vs. 3.5 Ϯ 1.31 units). Quantitative analysis of macrophage ED-1-positive cells and proliferating cell nuclear antigen using immunohistochemistry demonstrated increased macrophage numbers in the renal interstitium (106.4 Ϯ 11.4 vs. 58.7 Ϯ 5.0 cells/mm 2 ) and increased proliferating cell number in cortical tubules (37.8 Ϯ 5.7 vs. 24.2 Ϯ 2.1 cells/mm 2 ), renal cortical vessels (2.2 Ϯ 0.5 vs. 0.13 Ϯ 0.07 cells/vessel), and the cortical interstitium (33.6 Ϯ 5.7 vs. 4.2 Ϯ 1.4 cells/mm 2 ) of hypertensive rat kidneys. These findings demonstrate that the renal pathological changes that occur during the development of malignant hypertension in Cyp1a1-Ren2 rats are characterized by inflammation and cellular proliferation in cortical vessels and tubulointerstitium. kidney; glomerulosclerosis; renal injury; immunohistochemistry; renin-angiotensin system; renal pathology; peptide hormones TRANSGENIC RATS WITH INDUCIBLE activation of extrarenal renin gene expression [TGR(Cyp1a1Ren2)] were generated using a renin transgene under the transcriptional control of the cytochrome P-450 (Cyp1a1) promoter (23). This transgenic rat line was created by inserting a mouse Ren2 renin gene, fused to an 11.5-kb fragment of the Cyp1a1 promoter, into the genome of the Fischer 344 rat (23). Cyp1a1, which catalyzes the oxidation of a wide range of endogenous lipophilic compounds and xenobiotics (7, 10, 43), is not constitutively expressed but is highly inducible on exposure to various aryl hydrocarbons such as indole-3-carbinol (I3C) (7,10,14,21,26,33,43). Induction of Cyp1a1 is mediated by the aryl hydrocarbon receptor, which is a basic helix-loop-helix-transcription factor that binds to specific DNA elements in the Cyp1a1 promoter (7, 13, 43). Rats transgenic for the Cyp1a1-Ren2 construct do not constitutively express the Ren2 renin gene. Rather, the Ren2 gene is expressed, primarily i...

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A genetic model of malignant phase hypertension in rats

Cited by 37 publications

References 29 publications

Genetic Clamping of Renin Gene Expression Induces Hypertension and Elevation of Intrarenal Ang II Levels of Graded Severity in Cyp1a1-Ren2 Transgenic Rats

Genetic Clamping of Renin Gene Expression Induces Hypertension and Elevation of Intrarenal Ang II Levels of Graded Severity in Cyp1a1-Ren2 Transgenic Rats

Controlled Hypertension, a Transgenic Toggle Switch Reveals Differential Mechanisms Underlying Vascular Disease

Renal vascular and tubulointerstitial inflammation and proliferation in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension

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