Efficient Liver-specific Deletion of a Floxed Human Angiotensinogen Transgene by Adenoviral Delivery of Cre Recombinasein Vivo

Stec, David E.; Davisson, Robin L.; Haskell, Ronald E.; Davidson, Beverly L.; Sigmund, Curt D.

doi:10.1074/jbc.274.30.21285

Cited by 83 publications

(96 citation statements)

References 36 publications

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“…11 The liver-specific ablation of human angiotensinogen gene flanked by loxP sites in transgenic mice using an adenovirus (1.1 Â 10 11 PFU) expressing Cre recombinase (Ad-CMVCre) has also been reported. 12 Presently in a majority of studies involving the CreloxP system, LacZ and fluorescent proteins (eg GFP) are being used as the reporter gene. 13 The use of theses reporters requires killing the animals and ex vivo analysis for reporter gene expression.…”

Section: Introductionmentioning

confidence: 99%

MicroPET imaging of Cre–loxP-mediated conditional activation of a herpes simplex virus type 1 thymidine kinase reporter gene

et al. 2004

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Section: Introductionmentioning

confidence: 99%

MicroPET imaging of Cre–loxP-mediated conditional activation of a herpes simplex virus type 1 thymidine kinase reporter gene

et al. 2004

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“…The TALH-HHO1 construct was isolated from the plasmid vector by digestion with BssHI and then purified and injected into fertilized mouse embryos using established transgenic techniques. 31 TALH-HHO1 mice were derived on a mixed B6SJL genetic background and bred back to C57BL/6J mice for greater than 10 generations.…”

Section: Generation Of Talh-hho1 Transgenic Micementioning

confidence: 99%

Expression of Heme Oxygenase-1 in Thick Ascending Loop of Henle Attenuates Angiotensin II-Dependent Hypertension

Stec

Drummond

Gousette

et al. 2012

Journal of the American Society of Nephrology

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Kidney-specific induction of heme oxygenase-1 (HO-1) attenuates the development of angiotensin II (Ang II) -dependent hypertension, but the relative contribution of vascular versus tubular induction of HO-1 is unknown. To determine the specific contribution of thick ascending loop of Henle (TALH) -derived HO-1, we generated a transgenic mouse in which the uromodulin promoter controlled expression of human HO-1. Quantitative RT-PCR and confocal microscopy confirmed successful localization of the HO-1 transgene to TALH tubule segments. Medullary HO activity, but not cortical HO activity, was significantly higher in transgenic mice than control mice. Enhanced TALH HO-1 attenuated the hypertension induced by Ang II delivered by an osmotic minipump for 10 days (13963 versus 15362 mmHg in the transgenic and control mice, respectively; P,0.05). The lower blood pressure in transgenic mice associated with a 60% decrease in medullary NKCC2 transporter expression determined by Western blot. Transgenic mice also exhibited a 36% decrease in ouabain-sensitive sodium reabsorption and a significantly attenuated response to furosemide in isolated TALH segments,. In summary, these results show that increased levels of HO-1 in the TALH can lower blood pressure by a mechanism that may include alterations in NKCC2-dependent sodium reabsorption. Heme oxygenase (HO) is the rate-limiting enzyme in the catabolism of heme to biliverdin, during which both carbon monoxide (CO) gas and free iron are released. Biliverdin is then reduced to bilirubin by the ubiquitous enzyme biliverdin reductase. There are two major isoforms of HO that are responsible for the breakdown of heme, HO-1 and HO-2. HO-2 is the constitutively expressed isoform, whereas HO-1 is inducible by a wide variety of stimuli, including hypoxia, metals, ischemia, and oxidative stress. In the kidney, both isoforms of HO are present, with the highest level of expression of both isoforms in the renal medulla under basal conditions. 1,2 HO enzymes are not only expressed in the renal medulla, but their metabolites, CO and bilirubin, play an important role in the regulation of both renal vascular and tubular function. Renal medullary infusion of the general HO inhibitor, zinc deuteroporphyrin 2,4-bis glycol, results in a significant decrease in renal medullary blood flow. 1 In the renal tubules, increases in perfusion pressure increase CO levels, and inhibition of HO activity results in significant attenuation of pressure natriuresis and development of salt-sensitive hypertension. 3

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“…Infants born to women receiving angiotensin converting enzyme (ACE) inhibitors demonstrated renal tubular dysgenesis very similar to that seen in the reported cases of NH (12). The liver is an integral part of the renin-angiotensin system in that it is the site of synthesis of most of all circulating angiotensinogen (AGT) (13) and thus is potentially pivotal in renal development. This study examined the hypothesis that fetal liver injury in NH impairs proximal renal tubular development via impaired hepatic AGT elaboration.…”

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Relationship of Proximal Renal Tubular Dysgenesis and Fetal Liver Injury in Neonatal Hemochromatosis

2010

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Renal tubular dysgenesis has been reported in isolated cases of neonatal hemochromatosis (NH). We hypothesized that fetal liver injury in NH impairs proximal renal tubular development via impaired hepatic angiotensinogen (AGT) elaboration. Morphometric analyses were performed of postmortem liver and kidney sections of cases of proven NH and postconception age-matched controls for renal proximal tubule density, hepatocyte mass, and hepatic AGT expression. Proximal tubule density was markedly reduced in NH cases, although they showed a spectrum from mild to severe paucity. Hepatic AGT expression was markedly reduced in NH cases and correlated closely with reduced hepatocyte mass. A linear relationship was established between hepatic AGT expression and the degree of renal tubular dysgenesis suggesting that there is a relationship between them. Our results demonstrate that there is a spectrum of kidney pathology in patients with NH including a large proportion of cases with severe proximal tubular dysgenesis. Hepatic synthetic failure resulting in insufficient production of AGT to support renal tubular development is the likely mechanism of kidney disease in NH. (Pediatr Res 67: [188][189][190][191][192][193] 2010) N eonatal hemochromatosis (NH) is defined by the presence in newborns of liver disease in association with pathologic siderosis of various organs and tissues in a pattern similar to hereditary hemochromatosis (1). NH has also been called "neonatal iron storage disease" and "perinatal hemochromatosis" on the basis of these unique pathologic findings. NH is invariably associated with severe liver injury, which evidently is initiated during fetal life (2). Current thinking is that gestational alloimmune hepatocyte injury is involved in the pathogenesis of most or all cases of NH (3,4).Several clinical observations date the onset of liver injury in NH to midgestation. One such observation is the postmortem finding of renal tubular dysgenesis reported in five neonates with NH (5-7). The hallmark histopathologic findings of renal tubular dysgenesis are paucity or absence of proximal tubules and the absence of necroinflammatory disease that could otherwise account for tubular loss. The proximal tubules in this condition appear short and poorly developed, with reduced convolution leading to reduced number of tubular profiles in histologic sections (8). These findings suggest that renal development has been arrested at 20-to 25-wk gestation. Assuming that failed renal development in renal tubular dysgenesis associated with NH is the result of or a complication of fetal liver injury, the finding dates the liver injury in these cases to around 20-wk gestation (9). That raises the question of whether renal development is affected in more cases of NH than is reflected in the meager case reports. In addition, the mechanism by which fetal liver injury leads to a rather specific pattern of failed development in the kidney deserves to be addressed. Renal tubular development is dependent on an intact renin-ang...

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Efficient Liver-specific Deletion of a Floxed Human Angiotensinogen Transgene by Adenoviral Delivery of Cre Recombinasein Vivo

Cited by 83 publications

References 36 publications

MicroPET imaging of Cre–loxP-mediated conditional activation of a herpes simplex virus type 1 thymidine kinase reporter gene

MicroPET imaging of Cre–loxP-mediated conditional activation of a herpes simplex virus type 1 thymidine kinase reporter gene

Expression of Heme Oxygenase-1 in Thick Ascending Loop of Henle Attenuates Angiotensin II-Dependent Hypertension

Relationship of Proximal Renal Tubular Dysgenesis and Fetal Liver Injury in Neonatal Hemochromatosis

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