Angiotensinogen gene null-mutant mice lack homeostatic regulation of glomerular filtration and tubular reabsorption

Okubo, Soichiro; Niimura, Fumio; Matsusaka, Taiji; Fogo, Agnes B.; Hogan, Brigid L.M.; Ichikawa, Iekuni

doi:10.1046/j.1523-1755.1998.00788.x

Cited by 75 publications

(49 citation statements)

References 16 publications

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“…This finding agree with prior studies that the absence of At1a receptors for AngII produces a state of sodium sensitivity in which alterations in sodium intake cause marked fluctuations in BP and At1a receptors expressed on renal vasculature and/or renal epithelia may play a critical role in sodium and volume homeostasis (31). Moreover, in agreement with this notion, whole kidney GFR and the size of glomerular tufts of AtgϪ/Ϫ mice were found to change markedly in response to altered salt intake (32).…”

Section: Discussionsupporting

confidence: 92%

Alterations in Renal Endothelial Nitric Oxide Synthase Expression by Salt Diet in Angiotensin Type-1a Receptor Gene Knockout Mice

Satô

Kihara²,

Hashimoto³

et al. 2004

Journal of the American Society of Nephrology

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Abstract. The effects of altered dietary salt intake and/or hydralazine-induced hypotension on renal endothelial nitric oxide synthase (eNOS) expression were determined in angiotensin type-1a receptor gene knockout (At1aϪ/Ϫ) and wild-type (At1aϩ/ϩ) mice. In At1aϪ/Ϫ mice, the levels of renal cortical eNOS mRNA and protein were 5 times and 3.5 times higher, respectively, in the high-salt (4% NaCl) group than in the low-salt group (0.3% NaCl). Systemic BP of the high-salt group (105 Ϯ 4.4 mmHg) was significantly higher than that of the low-salt group (77.0 Ϯ 4.7 mmHg). When hydralazine was administered to the mutant mice fed a high-salt diet, BP was reduced to 72.5 Ϯ 1.3 mmHg, with decreases in the levels of renal eNOS mRNA and protein expression to about half of those found in nontreated group. Consistent with the results for eNOS mRNA and protein expression, nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase activity and eNOS immunoreactivity localized in the endothelium of the renal vasculature changed parallel with the amount of salt intake. In contrast to mutant mice, At1aϩ/ϩ mice did not show any changes in renal eNOS expression during the manipulation of salt intake and/or hydralazine-induced hypotension. These results suggest that At1a receptor-mediated inputs play critical roles in maintaining renal vascular eNOS expression and activity during changes in salt-water balance and systemic BP.The endothelial nitric oxide synthase (eNOS) is distributed throughout the renal vasculature, from the renal arterial branches to the glomerular capillaries. NO synthesized by eNOS in response to renal perfusion pressure and the tubuloglomerular feedback system is thought to be an important modulator of vascular tone. Renal perfusion pressure has been shown to increase urinary NO 2 /NO 3 excretion as well as output current from an electrode inserted into the renal cortex (1).eNOS is a constitutively expressed enzyme responsible for the generation of basal NO release from endothelial cells. The major stimuli of enzyme activity include shear stress and/or pressure stretch. In the kidney, however, the regulation of eNOS activity under various physiologic conditions is not well understood. Previous experiments testing the effects of altered salt intake or BP on renal eNOS activity have yielded inconsistent results (2-8).While there is little information on the endogenous factors that regulate eNOS expression within the kidney, angiotensin II

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Section: Discussionsupporting

confidence: 92%

Alterations in Renal Endothelial Nitric Oxide Synthase Expression by Salt Diet in Angiotensin Type-1a Receptor Gene Knockout Mice

Satô

Kihara²,

Hashimoto³

et al. 2004

Journal of the American Society of Nephrology

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“…Mice lacking AGT (Agt−/−) have severe hypotension and overexpress renin [22][23][24]. These mice also have a high rate of neonatal mortality associated with an impaired ability to concentrate urine, and have severe renal abnormalities including hydronephrosis, and hypertrophy of renal arteries [23,25].…”

Section: Angiotensinogen (Agt)mentioning

confidence: 99%

The Renin Angiotensin System and the Metabolic Syndrome~!2010-02-12~!2010-04-19~!2010-06-25~!

Wang¹,

Li²,

Takahashi³

2010

TOHYPERJ

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“…[7][8][9] For example, AOGEN-null mice display lesions in the renal cortex, interstitial inflammation, tubular atrophy, reduced renal papillary, and hypotension. 10,11 Knockout mice, which lack AT 1 expression, show a phenotype similar to that of mice lacking AOGEN and ACE gene expression. [12][13][14][15][16] These animals present hypotension, shorter survival, and marked abnormalities in renal development.…”

mentioning

confidence: 93%

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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Angiotensinogen gene null-mutant mice lack homeostatic regulation of glomerular filtration and tubular reabsorption

Cited by 75 publications

References 16 publications

Alterations in Renal Endothelial Nitric Oxide Synthase Expression by Salt Diet in Angiotensin Type-1a Receptor Gene Knockout Mice

Alterations in Renal Endothelial Nitric Oxide Synthase Expression by Salt Diet in Angiotensin Type-1a Receptor Gene Knockout Mice

The Renin Angiotensin System and the Metabolic Syndrome~!2010-02-12~!2010-04-19~!2010-06-25~!

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

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