The use of transgenic animal models to study the role that specific genes play in causing hypertension has been a focus of much research. However, to our knowledge there are no studies in which the mice were allowed to age. With the exception of a few models that are severely hypertensive and will not survive more than a few weeks or months, the lack of data in aging hypertensive trans-genics likely reflects the specific interest of the investigators who developed the strains; that is, the animals were developed to answer a question not involving aging. Following we describe the most common transgenic hypertensive strains.
Models transgenic for genes of the renin-angiotensin system
TGR(mREN2)27. TGR(mREN2)27 is the first rat model of hypertension caused by a defined genetic defect. The TGR(mREN2)27 harbors the murine Ren-2 gene on the genetic background of the SD rat. These transgenic rats develop fulminant hypertension at an early age despite low levels of renin in plasma and kidney. High expression of the renin transgene in extrarenal tissues is associated with increased local formation of angio-tensin II, which suggests that activated extrarenal RAS might be responsible for the hypertensive phenotype. In heterozygous animals, hypertension is evident at four to five weeks of age, reaching maximum values at eight to nine weeks (systolic BP: 240 mmHg in males and 200 mmHg in females). The phase of established hypertension is followed by a decrease in blood pressure by 20 to 30 mmHg in male and 40 to 60 mmHg in female TGR(mREN2)27 between 20 and 24 weeks of age. At 42 weeks of age, the male TGR(mREN2)27 are hypertensive, whereas blood pressure levels in female transgenic rats are not different from those found in age-matched SD rats (Lee et al., 1996).
TGR(hAOGEN-hREN). The TGR(hAOGEN-hREN) is a model of high human renin hypertension in the rat. This strain resulted from a cross between transgenic rats harboring human angiotensinogen gene and human renin gene, respectively. The offspring from this cross harbor both transgenes and have all the necessary components of the human renin angiotensin system to generate angiotensin II. The TGR(hAOGEN-hREN) rats have severe hypertension and hypertensive end-organ damage and die after about eight weeks, unless treated with converting enzyme inhibitors. Although useful for pharmacological investigation of the human renin angiotensin system, this rat model is not well suited for aging studies, due to their short survival (Bohlender et al., 1997).
Mice transgenic for both human renin and angio-tensinogen genes. Sigmund et al. developed transgenic mice expressing both human renin and angiotensinogen genes that are markedly hypertensive and exhibit high plasma concentrations of angiotensin II (Sigmund et al., 1992). These animals also display hypertensive end-organ damage and endothelial dysfunction. Transgenic mice harboring an artificial chromosome encoding human renin together with the next upstream and downstream genes in order to ensure appropriate regulation of the renin transgene display a modest increase in blood pressure when crossed with human angiotensinogen-expressing mice. These data show that even small amounts of renin could cleave increased amounts of angiotensinogen producing hypertension. To our knowledge, no aging studies have been performed using these animals.
Models transgenic for genes of the endothelin system. Elevated plasma endothelin concentrations have been associated with several cardiovascular diseases, including hypertension. A mouse model overexpressing endothelin-1 gene under the control of its own promoter has been characterized. These transgenic mice exhibit two-fold increases in endothelin-1 concentration in plasma, aorta, heart, kidney, and intestine. Although the blood pressure and kidney morphology and function are normal in young (8 weeks old) transgenic mice, with aging (12-14 months old) they develop renal injury with glomerulosclerosis and interstitial fibrosis (Hocher et al., 1997). In addition, Shindo et al. showed that salt-sensitive hypertension develops with aging in these mice, perhaps secondary to nephron loss (Shindo et al., 2002). This model therefore might be useful for the study of the permissive role of the aging process on the endothelin-induced renal pathology and hypertension. However, there are currently no data using aging ET-1 overexpression mice.
The follitropin receptor knockout mouse (FORKO)— Model of postmenopausal hypertension. A genetic model of estrogen deficiency recently has been characterized for the study of menopausal hypertension. The FORKO mice exhibit a reduced production of estrogen due to the genetic inactivation of FSH receptors (Dierich et al., 1998). These mice have ovarian insufficiency, low estrogen levels with functionally active estrogen receptors, and increased testosterone levels. They also show osteoporosis, hypercholesterolemia, and weight gain consistent with the postmenopausal pathology in women. The FORKO mice have significantly elevated systolic and diastolic blood pressure at 14 to 16 weeks of age, as measured by telemetry (Javeshghani et al., 2003). Hypertension in this model is paralleled by vascular remodeling and altered contractile responses to angio-tensin II. The mechanisms of altered blood pressure regulation in the FORKO mice are not clear and might involve both estrogen deficiency and increased testosterone levels. There are no aging studies in these animals as yet.
Glial cell-line-derived neurotrophic factor heterozygotes (GDNF)—Model of reduced renal glomeruli. It has been hypothesized that low nephron number is a risk factor for the development of cardiovascular disease including hypertension. The GDNF has been shown to play a major role in kidney development (Treanor et al., 1996). Although homozygous null mutants for GDNF show bilateral renal agenesis and die shortly after birth, the heterozygous mice are fertile and viable but have a 30% reduction in the nephron endowment at 30 days of age, as compared to the wild-type controls (Pichel et al., 1996). The study of Cullen-McEwen et al. (2003) shows that at 14 months of age, the GDNF heterozygous mice have elevated blood pressure but preserved renal function as measured by GFR and RBF. These mice also display glomerular hypertrophy, probably due to the compensatory hyperfiltration. Therefore, the GDNF heterozygous mouse may be a useful tool to study the lifelong consequences of reduced nephron number on the development of hypertension.
There are several animal models of hypertension that would be conducive for aging studies. These include genetic models and nongenetic models of hypertension and transgenic models that exhibit hypertension. However, some of the genetically hypertensive models, such as the SHRSP and the Dahl salt-sensitive rats, have limited life spans that make them inappropriate for aging studies. Transgenic rats and mice are novel models in which to study specific systems known to be responsible for hypertension. However, there are very few aging studies in hypertensive transgenic animals, and whether these transgenics prove to be good models of aging and hypertension remains to be determined experimentally.
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