Transgenic Animals and Instrumentation Core Facility
Jasmina Varagic, MD, PhD
The Transgenic Animals and Instrumentation Core Facility provides investigators at the Wake Forest School of Medicine and other research facilities with transgenic (TG) rats having genetic alterations of the renin-angiotensin system. At present the Transgenic Rat Facility has breeding colonies for three different transgenic rats. In one of these the mouse renin-2 gene (mRen2) has been incorporated into the rat genome. These animals were originally developed by Drs. Mullins and Ganten (Nature 344:541-544, 1990) in Germany and are referred to as the (mRen2)27 TG rat. In these TG rats the mRen2 gene is expressed upon an outbred Hannover Sprague-Dawley (SD) background. We received breeder animals from Dr. Ganten in 1992 and have maintained a core breeder colony of (mRen2)27 TG rats homozygous for the mRen2 gene since that time. Homozygous (mRen2)27 TG rats are bred with Hannover SD rats to produce hemizygous (mRen2)27 TG rats that are made available for research purposes. The hemizygous (mRen2)27 TG rat has a phenotype typified by the development of hypertension as the rats attain sexual maturity. The (mRen2)27 TG rats exhibit a sexual dimorphism in this trait in that the hypertension is more extreme in males than females. The hypertension in male and female hemizygous offspring can be reversed by treatment with an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II AT1 receptor antagonist (AT1 ARB). The Transgenic Rat Facility also maintains a breeder colony of Hannover SD rats for the purpose of breeding with the (mRen2)27 TG homozygous rats as well as serving as the control line for the hemizygous (mRen2)27 TG rats. We have also developed the congenic mRen2.Lewis strain. The mRen2.Lewis rats were derived by backcrossing the original (mRen2)27 TG rat with Lewis rats. Thus, in the mRen2.Lewis rat the mRen2 gene is expressed upon a genetically homogenous Lewis background. We have a breeder colony of homozygous mRen2.Lewis TG rats which can be crossed with Lewis rats to produce hemizygous mRen2.Lewis TG rats that are available for research purposes. The Lewis rat serves as the control strain for the mRen2.Lewis TG rat. The hemizygous mRen2.Lewis rats have much the same phenotype as the original (mRen2)27 TG rat. That is, the hypertension is more extreme in males than females and the elevated blood pressure can be reversed by treatment with an ACE inhibitor. The third type of TG rat maintained by the Transgenic Rat Facility is the angiotensinogen antisense transgenic rat [TGR(ASrAogen)] which was also developed by Ganten and colleagues (PNAS 96:3975-3980, 1999). In this TG rat an antisense to angiotensinogen (Aogen) is driven by an astrocyte-specific promoter thereby assuring suppression of Aogen restricted to glial cells of the central nervous system. The Transgenic Rat Facility maintains a homozygous breeder colony of the TGR(ASrAogen) which are available for research studies. Schinke et al. (PNAS 96:3975-3980, 1999) originally described the phenotype of the TGR(ASrAogen) as having a modestly lower blood pressure, approximately 90% reduction in the production of Aogen in the brain whereas no alteration in Aogen synthesis in the liver or other tissues, and a mild form of diabetes insipidus. Drs. Kasper and Diz have more recently determined that the TGR(ASrAogen) have a number of additional important phenotypic features (FASEB J. 18:A738, 2004; Hypertension 44:503, 2004). The TGR(ASrAogen) do not develop insulin resistance; they have a significantly lower body weight as they age; and they exhibit superior cognitive function as they age. The control line for the TGR(ASrAogen) is the Hannover SD rat.
The (mRen2)27 TG, mRen2.Lewis TG, TGR(ASrAogen), and Hannover SD rats are all available to investigators for research purposes. Please contact Dr. Jasmina Varagic (336-716-2738; firstname.lastname@example.org), Director of the Transgenic Animals and Instrumentation Core Facility, if you are interested in using any of these rats.