HYPERTENSION IN THE TRANSGENIC RAT TGR(MREN-2)27 MAY BE DUE TO ENHANCED KINETICS OF THE REACTION BETWEEN MOUSE RENIN AND RAT ANGIOTENSINOGEN

The transgenic rat TGR(mRen-2)27, in which the Ren-2 mouse renin gene is transfected into the genome of the rat, develops severe hypertension with high adrenal renin and low kidney renin. These animals express both mouse and rat renin. To investigate the cause of hypertension in the TGR rat, we compared the kinetics of mouse renin acting on mouse and rat angiotensinogens. The optimum pH of the renin reaction in the Sprague-Dawley rat was 6.5, whereas the optimum pH of the reaction in the TGR rat was approximately 8.5. The optimum pH of the renin reaction in the DBA mouse was 6.0. Purified mouse Ren-2 renin acting on rat angiotensinogen showed a pH profile similar to that for the renin reaction in the TGR rat. The angiotensinogen concentration in pooled plasma from eight DBA mice was 104.5 ng angiotensin I/mL and was clearly lower than that in Sprague-Dawley rats (772.4+/-37.3 ng angiotensin I/mL, n=4). The reaction of purified mouse Ren-2 renin with rat angiotensinogen was 10 times faster than with mouse angiotensinogen. Plasma renin activity in DBA mice increased dramatically on addition of rat angiotensinogen (from 253.4+/-6.7 to 225 000+/-48 000 ng angiotensin I/mL per hour). Intravenous injection of 2 or 10 mu L of DBA mouse plasma into the nephrectomized Sprague-Dawley rat increased the mean arterial pressure of the rat by 27.7+/-4.7 and 61.81+/-2.7 mm Hg, respectively, whereas injection of 200 mu L Of Sprague-Dawley rat plasma did not change the mean arterial pressure of the rat. From these measurements and from the kinetic parameters measured by Poulsen and Jacobsen (J Hypertens. 1986;4:175-180), we conclude that the molar concentration of mouse renin in the TGR rat is low compared with that of rat renin (1.5 versus 5.0 pmol/L) but that this low level of circulating mouse renin contributes significantly to plasma renin activity in the TGR rat. The elevation of renin activity and resulting hypertension in the TGR rat therefore can be attributed to the enhanced kinetics of mouse renin acting on rat angiotensinogen.