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Curt D Sigmund

Publications and source records attributed to Curt D Sigmund.

61 records · Page 4Linked to original sources
PubMed2002

The brain renin-angiotensin system in transgenic mice carrying a highly regulated human renin transgene.

We previously reported the generation of 2 novel transgenic mouse models containing the human renin (hREN) gene encoded on P1 artificial chromosomes (PAC) containing large amounts of 5'-flanking DNA. These mice exhibit a very narrow tissue-specific expression profile and exhibit tightly regulated expression in kidney in response to physiological cues. In brain, transcription of hREN occurs from an alternative upstream promoter, causing translation to initiate within exon-II and potentially generating an intracellular form of active renin. Double transgenic mice containing a PAC transgene and the human angiotensinogen (hAGT) gene (P+/A+) are moderately hypertensive. We tested whether increased RAS activity in the brain contributes to the mechanism of hypertension in P+/A+ double transgenic mice. Expression of hREN mRNA in brain was confirmed in 4 independent PAC transgenic lines and utilization of the alternative transcription start site in brain was confirmed in each line. Human REN immunostaining was observed in the dorsal cochlear nucleus, hypothalamus, and cortex. P+/A+ mice exhibited a greater fall in mean arterial pressure after intracerebroventricular injection of losartan than controls. P+/A+ mice exhibited a greater drop in arterial pressure after intravenous injection of a vasopressin V(1) receptor antagonist, and an equivalent drop in arterial pressure after intravenous injection of a ganglion blocker compared with controls. These results support the hypothesis that renin is endogenously expressed in the brain and suggest that increased brain RAS activity may contribute to the maintenance of moderate hypertension in P+/A+ transgenic mice at least in part by a vasopressin-dependent mechanism.

Alternative Splicing↗
PubMed2002

Use of transgenic and knockout strategies in mice.

Over 2 decades ago mouse models were generated with an exogenous gene integrated into its genome to create the first transgenic mice. Since that time, new methods have been developed and old methods improved, allowing investigators more flexibility to answer important questions about physiology and gene function. Transgenic and knockout technology have been particularly useful in the kidney as various transgenic mouse models have been successfully generated to gain a better understanding of renal physiology at the gene level. Now with the sequencing of mammalian genomes at the forefront of science, the need for transgenic technology to understand gene function in the context of the whole animal will become increasingly more important. Therefore, this article focuses on some of the strategies that can be used when generating transgenic mouse models.

Animals↗
PubMed2002

Endothelial dysfunction and blood pressure variability in selected inbred mouse strains.

The genetic regulation of blood pressure (BP) and endothelial function is likely to be polygenic. Because there is considerable variability in basal BP among inbred mouse strains, the purpose of this study was to determine whether a similar variability in vascular function exists among 7 "normotensive" strains. We tested the hypothesis that compared with mice with higher BPs, mice with lower BPs would have greater aortic endothelial responses to acetylcholine (ACh). Mean BP ranged from 117 to 145 mm Hg among the 7 strains. The responses of aortic rings to ACh, sodium nitroprusside, and papaverine were assessed after submaximal precontraction with prostaglandin F(2alpha). The aortas from all strains relaxed in a concentration-dependent manner to sodium nitroprusside and papaverine, but responses to ACh were markedly impaired in the aortas, but not carotid arteries, from 129P3/J and 129X1/SvJ mice. Aortas from the other strains relaxed normally to ACh. Furthermore, the endothelium-dependent dilators ADP and A23187 caused similar relaxation in 129P3/J, 129X1/SvJ, and C57BL/6J mice. Although the data do not support the initial hypothesis, the impaired aortic response to ACh in the 129 strains is a novel finding and illustrates the potential impact that genetic background can have on vascular responsiveness.

Acetylcholine↗
PubMed2002

Lower blood pressure in floxed angiotensinogen mice after adenoviral delivery of Cre-recombinase.

Recent experimental evidence suggests a role for tissue renin-angiotensin systems in the development of hypertension. To test the importance of tissue renin-angiotensin systems in the development and maintenance of angiotensin II-dependent hypertension, we generated a transgenic model in which exon 2 of the human angiotensinogen gene is flanked by loxP sites (hAGT(flox)) so that this region of the gene can be deleted by the cre-recombinase. Double transgenic human renin and hAGT(flox) (R(+)/A(+flox)) mice of two independent lines exhibited elevated blood pressure. Acute administration of an adenovirus containing cre-recombinase (Adcre) lowered blood pressure by 30 mm Hg over a 4-day period as measured with fluid filled catheters. The chronic effect of Adcre administration on blood pressure was determined by radiotelemetry in a separate group of R(+)/A(+flox) mice. Blood pressure decreased by 25 mm Hg from baseline by day 8 post-Adcre, but increased on each day thereafter until it was 90% of baseline by day 21 post-Adcre. Expression analysis indicated the absence of detectable hAGT mRNA in the liver at day 5 post-Adcre, but reappeared at normal levels at days 14 to 21 post-Adcre. These studies suggest that Adcre is effective for acute, but not chronic, elimination of hepatic hAGT. Chronic elimination of hepatic hAGT will likely require the use of transgenic mice endogenously expressing cre-recombinase in the liver.

Adenoviridae↗
PubMedDate not supplied

Angiotensin mutant mice: a focus on the brain renin-angiotensin system.

With advances in genetic manipulation and molecular biological and physiological techniques, the mouse has become the animal model of choice for studying the genetic basis of human diseases. The two most commonly used methods for analyzing the function of a gene in vivo, overexpression (transgenic mouse) and deletion (knockout mouse), have been extremely useful in establishing the importance of genes in genetic disorders. The renin-angiotensin system (RAS) is one of the most widely studied systems controlling blood pressure. Although the primary site of Ang-II production is the plasma, all the components of the RAS cascade are expressed in many tissues, including the brain. This review briefly summarizes systemic and tissue-specific transgenic and knockout mouse models of the RAS for determining the role of this system in the regulation of blood pressure and in the pathogenesis of hypertension, with a focus on the RAS in the brain.

Angiotensins↗