Increased vascular angiotensin formation in female rats harboring the mouse Ren-2 gene.

Abstract

Rats harboring the mouse Ren-2 transgene develop hypertension despite low levels of plasma renin activity. We tested the hypothesis that these rats exhibit an increase in vascular angiotensin formation caused by the presence of the transgene. We measured the release of angiotensins I and II from isolated perfused hindquarters by high-performance liquid chromatography and radioimmunoassay. Female rats heterozygous for the transgene had significantly elevated mean arterial pressure compared with control rats (189.3±9.5 versus 110.0±5.4 mm Hg, p<0.05). Plasma angiotensin II was significantly decreased in transgenic rats. Transgenic rat hindquarters released more angiotensin I (121±37 versus 39±12 fmol/30 min, n=7 each) and more angiotensin II (210±21 versus 62±12 fmol/30 min,/?<0.05, n-1 each) than control rat hindquarters. Captopril increased angiotensin I release and decreased angiotensin II values in both transgenic and control rat hindquarters. Bilateral nephrectomy 24 hours before hindquarter perfusion greatly reduced angiotensin release from control rat hindquarters but not from transgenic rat hind limbs. We also tested for the presence of Ren-2 messenger RNA in mesenteric and aortic tissue by RNase protection assay and Northern blot analysis. We found that Ren-2 messenger RNA was present in mesenteric and aortic tissue of transgenic but not of control rats. We conclude that the Ren-2 transgene is expressed in vascular tissue of transgenic rats and may be responsible for substantial increases in vascular angiotensin formation. (Hypertension 1992; 19:687-691) KEY WORDS • transgenic animals • renin • hind limb • converting enzyme inhibition R ecently, Mullins et al 1 were successful in producing rats transgenic for the mouse Ren-2 gene. These rats develop severe hypertension; however, they exhibit low, rather than elevated, plasma levels of renin and circulating angiotensin II (Ang II) despite the expression of the Ren-2 gene in several tissues.1 Nevertheless, the hypertension in these rats is readily responsive to low doses of angiotensin converting enzyme inhibitors.1 However, no evidence has been published that Ang II production is increased in these animals.During the past decade, attention has been drawn to local renin and angiotensin formation. Such systems have been described in the brain, heart, adrenal gland, and walls of blood vessels.2 " 5 However, the role of local Ang II production in the regulation of vascular tone remains unclear. We and others have used the isolated perfused rat hindquarter to demonstrate the activity of the vascular renin system by measuring local formation of angiotensin peptides. 5 -7 In the current study, we tested the hypothesis that rats transgenic for the mouse Ren-2 gene exhibit an increased formation of angiotensin peptides within the walls of blood vessels. We examined angiotensin release from isolated perfused rat hindquarters and demonstrated the expression of the transgene within the vessels of these rats. Our results provide direct evidence for increased blood...

Vascular damage without hypertension in transgenic rats expressing prorenin exclusively in the liver.

“…These rats were severely hypertensive and had target organ damage. Transgene expression levels varied in different organs involved in blood pressure homeostasis, including adrenals, kidneys, brain, and blood vessel walls, and plasma prorenin was considerably increased (28)(29)(30)(31). To further understand the involvement of the RAS in hypertension, we focused our attention on the contribution of elevated prorenin (plasma and tissue) to blood pressure elevation and on the role of extrarenal renin in blood pressure regulation.…”

Renal injury in streptozotocin-diabetic Ren2-transgenic rats is mainly dependent on hypertension, not on diabetes

“…This observation was somewhat unexpected. In many years of experience with both methods, we have usually obtained a good correlation between tail-cuff systolic blood pressure and intra-arterial measurements in several rat models of hypertension (11,12,24,34). We cannot explain this discrepancy in the case of losartan-treated STZ-TGR, but this finding certainly underscores the importance of the recent recommendation (20) not to rely on tail-cuff measurements alone.…”

Oxidative stress contributes to pulmonary hypertension in the transgenic (mRen2)27 rat

“…This pattern suggests that local transgene expression leads to development of hypertension (79) and end-organ damage in the heart (53) and kidneys (4). Furthermore, the ren2 transgene is expressed in vascular tissue and appears to be responsible for substantial increases in ANG II formation within the vascular wall (23). Finally, hypertension in Ren2 rats develops, despite low levels of circulating ANG I and normal levels of ANG II (40).…”