Abnormal water metabolism in mice lacking the type 1A receptor for ANG II

Oliverio, Michael I.; Delnomdedieu, Marielle; Best, Christopher F.; Li, Ping; Morris, Mariana; Callahan, Michael F.; Johnson, G. Allan; Smithies, Oliver; Coffman, Thomas M.

doi:10.1152/ajprenal.2000.278.1.f75

Cited by 85 publications

(109 citation statements)

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“…42 Complete deletion of the AT 1a receptor resulted in an animal with enhanced osmotic and sympathetic responses, as well as altered renal function. 18,19,44 However, there are limits to the use of these genetic models. First, because AT 1 receptors are widely expressed in brain and periphery, it is difficult to determine the regional functionality in models in which the receptor is globally deficient.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, studies in mice lacking AT 1a receptors show that water intake is also increased, similar to that seen in mice exposed to Ad-AT 1a -shRNA. 44 This may be related to changes in renal function or to changes in the brain reninangiotensin system. 44 Davisson et al 17 showed that brain AT 1b receptors are important in the mediation of the Ang IIinduced drinking responses.…”

Section: Discussionmentioning

confidence: 99%

“…44 This may be related to changes in renal function or to changes in the brain reninangiotensin system. 44 Davisson et al 17 showed that brain AT 1b receptors are important in the mediation of the Ang IIinduced drinking responses. The current observation that inhibition of AT 1a receptors in the SFO produced an increase in water intake could result from an enhancement in Ang AT 1b signaling.…”

Section: Discussionmentioning

confidence: 99%

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Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT _1a Receptors in Mouse Brain

Chen

Hoffmann

et al. 2006

Hypertension

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Abstract-Because of the lack of pharmacological approaches, molecular genetic methods have been required to differentiate between angiotensin type 1(AT 1 ) receptor subtypes AT 1a and AT 1b . RNA interference is a new tool for the study of gene function, producing specific downregulation of protein expression. In this study, we used the small hairpin RNA (shRNA) cassette method to screen target sites for selectively silencing AT 1a or AT 1b receptor subtypes in cultured Neuro-2a cells using real-time RT-PCR. For in vivo functional studies, we used C57BL mice with arterial telemetric probes and computerized licking monitors to test the effect of adenovirus carrying the DNA sequence coding AT 1a shRNA (Ad-AT 1a -shRNA). Ad-AT 1a -shRNA was injected into the lateral ventricle (intracerebroventricular) or the brain stem nucleus tractus solitaries/dorsal vagal nucleus (NTS/DVN) with measurement of water intake, blood pressure (BP), and heart rate (HR) for up to 20 days after injection. Tissue culture studies verified the specificity and the efficiency of the constructs. In animal studies, ␤-galactosidase staining and Ang receptor binding assays showed expression of shRNA and downregulation of Ang AT 1 receptors in the subfornical organ and NTS/DVN by Ͼ70%. Intracerebroventricular injection of Ad-AT 1a -shRNA increased water intake with no effect on BP or HR. In contrast, microinjection of Ad-AT 1a -shRNA into NTS/DVN caused a decrease in BP with no effect on HR or water intake. Results demonstrate the use of the RNA interference method in site-directed silencing of gene expression and provide a method for the in vivo study of Ang AT 1 receptor function. Key Words: blood pressure Ⅲ brain Ⅲ gene regulation Ⅲ renin-angiotensin system B rain angiotensin (Ang) has been implicated in the control of blood pressure (BP), water balance, and hormone secretion. 1-3 Ang type 1 (AT 1 ) receptors are richly expressed in several brain regions, including the subfornical organ (SFO), paraventricular nucleus (PVN), dorsal nucleus vagus (DVN), nucleus tractus solitarii (NTS), and locus coeruleus. 4,5 In rodents, 6 and perhaps in humans, 7,8 there are 2 related AT 1 receptors subtypes, AT 1a and AT 1b . Recent studies by us 4,5 and others 9 demonstrate that AT 1 receptor subtypes AT 1a and AT 1b have similar distribution patterns in the mouse brain. In addition, several lines of reports showed that AT 1a and AT 1b receptor subtypes exhibit individual regulatory functions. 10 -12 Our previous results demonstrated that AT 1a and AT 1b receptors are differentially expressed in response to increased dietary salt and fluid deprivation within mouse brain areas, such as the hypothalamus, anterior pituitary, and brain stem. 4,5,13 However, the precise functional roles of brain AT 1a and AT 1b receptors in specific brain regions remain to be determined.AT 1a and AT 1b receptors share 95% homology in mRNA and amino acid sequences and have similar Ang II binding characteristics. 14 It is difficult to differentiate the subtypes, because there are ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT _1a Receptors in Mouse Brain

Chen

Hoffmann

et al. 2006

Hypertension

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“…Urine of male and female mPges1 ϩ/ϩ and mPges1 Ϫ/Ϫ mice was collected by bladder massage before and after a 12-h period of water deprivation. Urine osmolalities were then immediately measured using a vapor pressure osmometer (Wescor Instruments, Logan, UT) as described previously (25).…”

Section: Assessment Of Urinary Concentrating Capacitymentioning

confidence: 99%

Role of Microsomal Prostaglandin E Synthase 1 in the Kidney

François

Facemire

Kumar

et al. 2007

Journal of the American Society of Nephrology

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Prostaglandin E 2 (PGE 2 ) is one of the most ubiquitous prostanoids in the kidney, where it may influence a wide range of physiologic functions. PGE 2 is generated through enzymatic metabolism of prostanoid endoperoxides by specific PGE synthases (PGES). Several putative PGES have been identified and cloned, including the membrane-associated, inducible microsomal PGES1 (mPGES1), which is expressed in the kidney. To evaluate the physiologic role of mPGES1 in the kidney, mice with targeted disruption of mPges1 gene were studied, with a focus on responses where PGE 2 has been implicated, including urinary concentration, regulation of blood pressure, and response to a loop diuretic. The absence of mPGES1 was associated with a 50% decrease in basal excretion of PGE 2 in urine (P < 0.001). In female but not male mPGES1-deficient mice, there was a reciprocal increase in basal excretion of other prostanoids. Nonetheless, urinary osmolalities were similar in mPges1 ؉/؉ and mPges1 ؊/؊ mice at baseline and after 12 h of water deprivation. Likewise, there were no differences in blood pressure between mPGES1-deficient and wild-type mice on control or high-or low-salt diets. The furosemide-induced increase in urinary PGE 2 excretion that was seen in wild-type mice was attenuated in mPGES1-deficient mice. However, furosemide-associated diuresis was reduced only in male, not female, mPGES1-deficient mice. Stimulation of renin by furosemide was not affected by mPGES1 deficiency. These data suggest that mPGES1 contributes to basal synthesis of PGE 2 , but there are other pathways that lead to renal PGE 2 synthesis. Moreover, there are significant gender differences in physiologic contributions of mPGES1 to control kidney function.

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“…Ang AT1a receptors are critical in the control of blood pressure, autonomic function, and fluid/electrolyte balance, as seen in studies of AT1a gene deletion models. 9,10 Ang AT2 receptors are more prevalent during development and are thought to mediate vasodilation and cell growth. 11,12 There is also evidence for interaction with ACE expression, with suggestions that AT2 activation decreases ACE activity.…”

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confidence: 99%

Novel Mass Spectrometric Methods for Evaluation of Plasma Angiotensin Converting Enzyme 1 and Renin Activity

2005

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Abstract-This article demonstrates the applicability of quantitative proteomics to assays of proteolytic enzyme activity.A novel assay was developed for measurement of renin and angiotensin-converting enzyme (ACE) activity in plasma.The method was validated in animal models associated with alterations of the renin angiotensin system (RAS). Using surface-enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF-MS) with a ProteinChip Array technology, plasma renin and ACE1 could be measured in Ͻ0.5 L of plasma. Plasma is incubated with peptide substrates for renin and ACE, tetradecapeptide (TDP), and angiotensin I (Ang I), respectively. The reactions mixtures are spotted onto the ProteinChip WCX2 and detected using SELDI-TOF-MS. Peak height or area under curve for TDP, Ang I, and angiotensin II (Ang II) peaks are measured. There was a linear relationship between disappearance of substrate and appearance of products for both renin and ACE (R 2 ϭ0.95 to 0.98). ACE1 activity was blocked with chelating agents (EDTA and 1,10 phenanthrolene), indicating action of a metalloprotease. The ACE1 inhibitor, captopril, selectively blocked ACE1. Renin activity was specifically blocked with renin inhibitor and was not affected by phenanthrolene or captopril. Animal models tested were Ang AT1a receptor-deficient and streptozotocin (STZ) diabetic mice. Plasma renin activity was increased Ͼ2-fold in AT1aϪ/Ϫ as compared with AT1a ϩ/ϩ . In STZ diabetic mice, ACE1 was increased 2-fold as compared with controls. The advantage of the method is that it is tagless, does not require additional purification steps, and is extremely sensitive. The approach can be multiplexed and used for identification of novel substrates/inhibitors of the RAS.

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Abnormal water metabolism in mice lacking the type 1A receptor for ANG II

Cited by 85 publications

References 34 publications

Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT _1a Receptors in Mouse Brain

Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT _1a Receptors in Mouse Brain

Role of Microsomal Prostaglandin E Synthase 1 in the Kidney

Novel Mass Spectrometric Methods for Evaluation of Plasma Angiotensin Converting Enzyme 1 and Renin Activity

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Abnormal water metabolism in mice lacking the type 1A receptor for ANG II

Cited by 85 publications

References 34 publications

Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT 1a Receptors in Mouse Brain

Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT 1a Receptors in Mouse Brain

Role of Microsomal Prostaglandin E Synthase 1 in the Kidney

Novel Mass Spectrometric Methods for Evaluation of Plasma Angiotensin Converting Enzyme 1 and Renin Activity

Contact Info

Product

Resources

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Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT _1a Receptors in Mouse Brain

Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT _1a Receptors in Mouse Brain