A transgenic rat line, TGR(mREN2)27, was established by introducing the murine Ren-2 gene into the genome of rats by microinjection techniques. These rats exhibit severe hypertension, making them an interesting model in which to study the role of renin in the pathophysiology of hypertension. However, although the additional renin gene is the only genetic difference compared with control rats, the exact mechanism of hypertension in TGR(mREN2)27 rats is still unclear. It cannot be attributed to a stimulation of the endocrine renin-angiotensin system or to an overexpression of renin in the kidney, since plasma and kidney renin and renin gene expression in the kidney are low in these animals. Here we describe recent progress made toward elucidating mechanisms of hypertension in TGR(mREN2)27 rats. 1) TGR(mREN2)27 rats were bred to homozygosity. The development of high blood pressure in homozygous rats is accelerated compared with that of heterozygous rats. This is paralleled by a higher mortality rate in homozygous TGR(mREN2)27 rats. Blood pressure and mortality rate of homozygous transgenic rats were effectively reduced by 10 mg captopril per kilogram body weight. 2) Treatment of 8-week-old heterozygous TGR(mREN2)27 rats with 10 mg/kg body wt per day of the angiotensin II receptor antagonist DuP 753 for 4.5 weeks normalized blood pressure. After withdrawal of the drug, blood pressure increased rapidly, reaching control levels after 3 weeks. In another group of TGR(mREN2)27 rats treated with 0.5 mg/kg per day, there was no change in blood pressure. Plasma renin and plasma angiotensin II were significantly higher in the high-dose group compared with the low-dose group. These data indicate that angiotensin II plays a major role in hypertension of TGR(mREN2)27 rats. 3) Because the activity of the plasma renin-angiotensin system is reduced in TGR(mREN2)27 rats but the pharmacological interventions with captopril and DuP 753 suggest an important role of angiotensin II for hypertension, our interest focused on tissue renin-angiotensin systems. By Northern hybridization, highest transgene expression was detected in the adrenal gland followed by thymus, tissues of the gastrointestinal and genital tracts, kidney, brain, and lung. No expression was found in the liver and submandibular gland. 4) Compared with Sprague-Dawley rats, urinary glucocorticoid and mineralocorticoid excretion was significantly enhanced in TGR(mREN2)27 rats up to an age of 18 weeks, suggesting that corticoids may be involved in the pathogenesis of hypertension in TGR(mREN2)27 rats. Treatment of 4- and 18-week-old TGR(mREN2)27 rats with the mineralocorticoid receptor antagonist spironolactone, however, did not influence blood pressure. The high expression of Ren-2 in the adrenal glands and the corticosteroid excretion analyses point to an important role of a local adrenal renin-angiotensin system in the pathophysiology of hypertension in TGR(mREN2)27 rats.