Differential evolution of blood pressure and renal lesions after RAS blockade in Lyon hypertensive rats

Bertram, D. S.; Blanc-Brunat, N; Sassard, J

doi:10.1152/ajpregu.00620.2001

Cited by 12 publications

(11 citation statements)

References 29 publications

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“…A similar perindopril efficiency has been reported in humans. 33,34 Taken together, the present study suggests that a link exists among ARAP1 gene expression, hypertension, and kidney hypertrophy.…”

Section: Discussionsupporting

confidence: 66%

Development of Hypertension and Kidney Hypertrophy in Transgenic Mice Overexpressing ARAP1 Gene in the Kidney

et al. 2006

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Abstract-Angiotensin II regulates blood pressure via activation of the type 1 receptor. We previously identified a novel angiotensin II type 1 receptor-associated protein and demonstrated that it promotes receptor recycling to the plasma membrane. To delineate the pathophysiological function of the ARAP1 in the kidneys, we generated transgenic mice that overexpress rat ARAP1 cDNA specifically in proximal tubules and tested the hypothesis that proximal tubule-specific overexpression of ARAP1 causes hypertension. Two lines of male transgenic mice, 650 and 670, displayed kidney-specific transgene expression. Systolic blood pressure was significantly elevated by Ϸ20 to 25 mm Hg in these lines of mice at 20 weeks of age compared with their nontransgenic litter mates. Urine volume, but not water intake, was significantly decreased in both lines compared with nontransgenic controls. The kidney/body weight ratio was significantly increased in both lines compared with their nontransgenic litter mates at 12 and 20 weeks of age. In contrast, no difference was observed in the ratio of brain, spleen, heart, and testis to body weight between male transgenic and nontransgenic animals. Inhibitions of the renin-angiotensin system completely normalized the systolic blood pressure of transgenic mice. Moreover, low salt intake prevented the development of hypertension, whereas high salt intake exacerbated the increase in blood pressure in transgenic mice. Therefore, our data show that proximal tubule-specific overexpression of ARAP1 leads to hypertension, suggesting that renal ARAP1 plays an important role in the regulation of blood pressure and renal function via activation of the intrarenal renin-angiotensin system. Key Words: animals, transgenic Ⅲ gene expression H ypertension is a major risk factor for cardiovascular and renal diseases. Although numerous studies have implicated a role for the renin-angiotensin system (RAS) in the development of hypertension, its mechanisms remain incompletely understood. Traditionally, the hypertensive effects of the RAS were considered to be the actions of circulating components of this system. According to this view, angiotensin II (Ang II) in the systemic circulation is generated from angiotensinogen (AOGEN), which is acted on by renin from the kidneys to proteolytically produce angiotensin I, a substrate being further processed by angiotensin-converting enzyme (ACE) to form biologically active Ang II. However, recent convincing evidence accumulated from physiological, biochemical, and molecular studies has demonstrated other pathways of Ang II production. Among these, the intrarenal RAS is of special interest. Renal proximal tubules contain all of the components of the RAS. [1][2][3] It has been demonstrated that activation of the Ang II type 1 receptor (AT 1 ) stimulates the apical sodium-hydrogen exchanger in proximal tubules 4 and augments epithelial sodium channel (ENaC) activity in the collecting ducts, 5,6 leading to modulation of blood pressure (BP) and fluid homeostasis. Furthermore...

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Section: Discussionsupporting

confidence: 66%

Development of Hypertension and Kidney Hypertrophy in Transgenic Mice Overexpressing ARAP1 Gene in the Kidney

et al. 2006

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“…39 -41 In contrast, studies in the Milan and Lyon hypertensive rats revealed that RAS blockade had no persistent effect on blood pressure despite marked improvements in indexes of vascular and renal injury. [42][43] To our knowledge, the present study is the first to demonstrate a substantial effect on blood pressure after cessation of AT 1 receptor blockade in adult females with established hypertension and in a hypertensive model other than the SHR. 38 Future studies are necessary to ascertain the mechanism and the duration of the persistent effects of olmesartan in the mRen (2).Lewis rat.…”

Section: Discussionmentioning

confidence: 56%

Estrogen or the AT1 Antagonist Olmesartan Reverses the Development of Profound Hypertension in the Congenic mRen2.Lewis Rat

et al. 2003

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Abstract-The influence of estrogen on the regulation of cardiovascular function remains a controversial and complex area of investigation. We assessed the effects of estrogen depletion in the congenic mRen(2).Lewis rat, established from the back-cross of the original (mRen2)-27 transgenic onto the Lewis inbred strain. Ovariectomy of heterozygous mRen(2).Lewis at 4 to 5 weeks resulted in a progressive increase in blood pressure compared with the sham surgery congenics at weeks 6 to 11. At 11 weeks, the ovariectomized mRen(2).Lewis (OVX) systolic blood pressure averaged 195Ϯ3.7 mm Hg versus 141Ϯ4.0 mm Hg for sham. Plasma Angiotensin (Ang) II, serum ACE activity, plasma renin concentration, as well as urinary excretion of Ang II, 8-isoprostane F 2␣ , and endothelin-1 were elevated; however, renal mRNA levels of eNOS were suppressed after ovariectomy. Estrogen replacement reduced blood pressure below both the sham and OVX by 11 weeks (125Ϯ2.9 mm Hg, nϭ7, PϽ0.01 versus OVX and sham). Moreover, the AT 1 receptor antagonist olmesartan (CS866; week 12 to 16) essentially normalized blood pressure to 113Ϯ5.4 mm Hg (nϭ6, PϽ0.01 versus OVX and sham). The attenuation of the hypertension was still evident 7 weeks after complete withdrawal of treatment (124Ϯ4.1 mm Hg at week 23). In summary, the OVX mRen.2.Lewis exhibited a rapid and sustained increase in blood pressure. Estrogen or olmesartan lowered pressure by a similar extent. We conclude that the ovary exerts considerable influence on the regulation of the blood pressure in the mRen2. Key Words: angiotensin II Ⅲ angiotensin-converting enzyme Ⅲ estrogen Ⅲ rats, transgenic Ⅲ hypertension, genetic I t is well recognized that ovarian hormones, particularly estrogen, exhibit a protective role on the cardiovascular system. After menopause, there is increased arterial pressure and higher rates of hypertension, renal disease, cardiovascular events, and mortality rates in women. However, recent clinical studies have questioned the beneficial effects of hormone replacement therapy (estrogen/progestin), particularly the actions that influence the cardiovascular system. 1 Indeed, one arm of the Women's Health Initiative (WHI) study with the combined therapy was halted prematurely because of negative outcomes, although the estrogen replacement group has continued at the present time. In light of the clinical data, the protective actions of estrogen would appear to be in contrast to the hormone's effects on several components of the renin-angiotensin system (RAS)-one of the key regulatory systems for the control of blood pressure and cardiovascular pathologies. Specifically, estrogen stimulates the expression of angiotensinogen from the liver, kidney, and other tissues, as well as increases renin activity. 2,3 However, estrogen has also been shown to suppress components of the RAS, including ACE and the AT 1 receptor, perhaps achieving an overall balance to attenuate the development of hypertension and progression of other cardiovascular events. 4 -7 Various hypertensive models have...

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“…200 mmHg), whereas the hypertension development in NIDDM is modest and progressive. The LH rat develops a mild hypertension (SBP 160-170 mmHg at adult age) associated with numerous metabolic risk factors and renal dysfunctions such as obesity, spontaneous hyperlipidemia, elevated glucose/insulin ratio, blunted pressurenatriuresis function, glomerular lesions and exaggerated urinary protein excretion [19][20][21][22][23]. It could be the fact that the development of a moderate NIDDM in LH rats might better reconcile the BP and metabolic disorders.…”

Section: Discussionmentioning

confidence: 99%

“…The blood pressure (BP) of LH rats is progressively elevated to reach a mild hypertension in adults associated with altered renal function, glomerular lesions and exaggerated urinary protein excretion [20][21][22][23]. In the present study, we aimed to develop, in LH rats in which the metabolic syndrome is genetically predisposed [19,20,24], a model of NIDDM by neonatal administration of STZ.…”

Section: Introductionmentioning

confidence: 99%

Neonatal streptozotocin-induced glucose intolerance: different consequences in Lyon normotensive and hypertensive rats

Emonnot¹,

Cohen

2007

Journal of Hypertension

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Differential evolution of blood pressure and renal lesions after RAS blockade in Lyon hypertensive rats

Cited by 12 publications

References 29 publications

Development of Hypertension and Kidney Hypertrophy in Transgenic Mice Overexpressing ARAP1 Gene in the Kidney

Development of Hypertension and Kidney Hypertrophy in Transgenic Mice Overexpressing ARAP1 Gene in the Kidney

Estrogen or the AT1 Antagonist Olmesartan Reverses the Development of Profound Hypertension in the Congenic mRen2.Lewis Rat

Neonatal streptozotocin-induced glucose intolerance: different consequences in Lyon normotensive and hypertensive rats

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