DEVELOPMENT OF A MODEL OF HUMAN RENIN-DEP ENDENT HYPERTENSION IN THE RAT

The effective development of human renin inhibitors meets its major ob stacle in the absence of a suitable experimental rodent model and the species-specificity of human renin, exclusively cleaving its natural s ubstrate human angiotensinogen. We have reconstructed the human renin- angiotensin system in transgenic rats over expressing the human angiot ensinogen gene TGR(hAOGEN) 1623 by chronically injecting i.v. human re combinant renin. We have first established new in vitro enzyme kinetic techniques to measure the various components of the chimeric renin-an giotensin system and distinguished the two human and rat-specific path ways of generating angiotensin 1 by the human specific renin inhibitor Ro 42-5892 (Hoffmann-La Roche). Male heterozygous TGR had plasma leve ls of rat angiotensinogen of 1.2 +/- 0.2 mg Ang l/ml while the plasma levels of the transgene were 141 +/- 98 mg Ang l/ml (n = 41; not norma lly distributed). Transgene expression was found in the liver kidney, aorta, heart and adrenals. Four rats were infused i.v. with human reco mbinant renin at 50 ng/h over 9 days which chronically increased their blood pressure to > 200 mmHg while total plasma renin activity increa sed by a factor of 300. Rat renin disappeared form the plasma. This ne w model of experimental human renin-induced hypertension in rats will facilitate the screening and characterization of human renin inhibitor s.