Significant Role of the Increase in Renin-Angiotensin System in Cardiac Hypertrophy and Renal Glomerular Sclerosis in Double Transgenic Tsukuba Hypertensive Mice Carrying Both Human Renin and Angiotensinogen Genes

Kai, Tatsuya; Kino, Hirofumi; Sugimura, Keiichi; Shimada, Sohei; Kurooka, Atsuhiro; Akamatsu, Kan-Ichiro; Takenaka, Toshihiko; Fukamizu, Akiyoshi; Murakami, Kazuo; Ishikawa, Kinji; Katori, Ryo

doi:10.3109/10641969809053223

Cited by 14 publications

(19 citation statements)

References 18 publications

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“…Furthermore, it has been reported that the inhibitory effect on the activity of ACE in the heart and kidney persists for a longer period than that in blood after administration of ACEI (45). Since ACEIs prevent left ventricular hypertrophy even at doses at which blood pressure does not fall (46,47), the suppression of tissue RAS is believed to be important for cardiac hypertrophic suppression, and reports supporting Kai et …”

Section: Discussionmentioning

confidence: 51%

Lisinopril Reduces Left Ventricular Hypertrophy and Cardiac Polyamine Concentrations without a Reduction in Left Ventricular Wall Stress in Transgenic Tsukuba Hypertensive Mice.

Kai

Ishikawa

2000

Hypertens Res

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This experiment was designed to determine how the angiotensin-converting enzyme inhibitor, lisinopril, acts on left ventricular wall stress and cardiac polyamine concentrations in Tsukuba hypertensive mice (THMs) carrying both human renin and angiotensinogen genes. Twelve-week-old THMs were treated with either lisinopril or hydralazine, or were left untreated, for 8 weeks. C57BL/6 mice of similar age were used as normal controls. Each group consisted of 14 mice. The systolic blood pressure of each mouse was meas-

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Section: Discussionmentioning

confidence: 51%

Lisinopril Reduces Left Ventricular Hypertrophy and Cardiac Polyamine Concentrations without a Reduction in Left Ventricular Wall Stress in Transgenic Tsukuba Hypertensive Mice.

Kai

Ishikawa

2000

Hypertens Res

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“…Conversely, transgenic mice carrying both human AOGEN and renin genes incur glomerulosclerosis and phenotypic alterations in mesangial cells. 17,18 Biochemical and pharmacological studies have revealed that AT 1 undergoes rapid internalization on agonist stimula-tion and then recycles back to the plasma membrane. 19 -22 Although the recycling of receptors to the plasma membrane is a notable event, the molecular mechanisms of this process are not well understood.…”

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confidence: 99%

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confidence: 99%

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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“…In THM, the occurrence of severe cardiac hypertrophy and glomerulosclerosis, in comparison with the degree of hypertension, has been reported. 3 L -158,809 [5,7-dimethyl-2-ethyl-3-[{2'-(1H-tetrazol-5-yl)is a selective AII receptor antagonist with high potency, good per os absorption, long duration and antihypertensive efficacy after a single dose equal to that of angiotensin converting enzyme inhibition, and does not have AII agonist activity. 4,5 The affinity of L-158,809 for the AII type 1 receptor (AT1R) and its potency for the inhibition of AII responses in a variety of tissues and in vitro preparations is subnanomolar (IC50=0.2-0.8 nmol/L).…”

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confidence: 99%

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confidence: 99%

Inhibitory Effects of a Subdepressor Dose of L-158,809, an Angiotensin II Type 1 Receptor Antagonist, on Cardiac Hypertrophy and Nephropathy Via the Activated Human Renin-Angiotensin System in Double Transgenic Mice With Hypertension

et al. 1998

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he Tsukuba hypertensive mouse (THM) is a hypertensive animal model prepared by introducing human renin and angiotensinogen genes into C57BL/6 mouse. 1 In THM, the cause of hypertension is known to be a single factor, an enhancement of the reninangiotensin system (RAS). In THM, angiotensin II (AII) is 3-5 times higher in serum and that in the heart and kidney is 4-5 times higher compared to C57BL/6 mice. 2 At 6 weeks of age, when blood pressure measurement becomes possible, THM already show elevated blood pressure. In THM, the occurrence of severe cardiac hypertrophy and glomerulosclerosis, in comparison with the degree of hypertension, has been reported. 3 L -158,809 [5,7-dimethyl-2-ethyl-3-[{2'-(1H-tetrazol-5-yl)is a selective AII receptor antagonist with high potency, good per os absorption, long duration and antihypertensive efficacy after a single dose equal to that of angiotensin converting enzyme inhibition, and does not have AII agonist activity. 4,5 The affinity of L-158,809 for the AII type 1 receptor (AT1R) and its potency for the inhibition of AII responses in a variety of tissues and in vitro preparations is subnanomolar (IC50=0.2-0.8 nmol/L). L-158,809 is 50-200 times more potent than losartan, an AT1R antagonist, and 5-15 times more potent than the metabolite, EXP3174. Indeed, the affinity of L-158,809 for AT1R is similar to that of the natural hormone, AII. With respect to the subtypes of AII receptors, L-158,809 has high selectivity for the AT1R, as does losartan, unlike PD-123,177 and PD-121,981, which are selective for AII type 2 receptor (AT2R). Unlike other AT1R antagonists, the inhibitory activity of L-158,809 is observed shortly after per os administration, and the duration of activity is greater than 24 h for both intravenous and per os administration. Moreover, the per os to intravenous potency ratio is 0.8. Therefore, L-158,809 is the most potent AT1R antagonist described to date.In the present study, L-158,809 was administered to THM, and its curative effects on cardiac hypertrophy and nephropathy were examined. Methods Animals and DrugsNine male THM were assigned to each of an L-158,809 dosage group (0.3 mg/kg per day) and a no-dosage group. Nine age-matched male C57BL/6 mice were used as normal controls. In the L-158,809 group, the drug was dissolved in drinking water and administered for 8weeks from the age of 20 weeks. All the mice were euthanized at 28 weeks of age. The mice were bred in an air-conditioned room at 22±2°C and humidity of 50±10%, with a 12-h light period (from 7.00 h to 19.00 h). They were fed a breeding The effects of L-158,809, an angiotensin II type 1 receptor antagonist, on cardiac hypertrophy and nephropathy were examined using Tsukuba hypertensive mice (THM) carrying both human renin and angiotensinogen genes. Nine male THM aged 20 weeks were assigned to each of a no-dosage group and an L-158,809 dosage group, and L-158,809 was administered for 8 weeks. Nine age-matched male C57BL/6 mice were used as normal control animals. At 28 weeks of age, all of the mice w...

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Significant Role of the Increase in Renin-Angiotensin System in Cardiac Hypertrophy and Renal Glomerular Sclerosis in Double Transgenic Tsukuba Hypertensive Mice Carrying Both Human Renin and Angiotensinogen Genes

Cited by 14 publications

References 18 publications

Lisinopril Reduces Left Ventricular Hypertrophy and Cardiac Polyamine Concentrations without a Reduction in Left Ventricular Wall Stress in Transgenic Tsukuba Hypertensive Mice.

Lisinopril Reduces Left Ventricular Hypertrophy and Cardiac Polyamine Concentrations without a Reduction in Left Ventricular Wall Stress in Transgenic Tsukuba Hypertensive Mice.

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

Inhibitory Effects of a Subdepressor Dose of L-158,809, an Angiotensin II Type 1 Receptor Antagonist, on Cardiac Hypertrophy and Nephropathy Via the Activated Human Renin-Angiotensin System in Double Transgenic Mice With Hypertension

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