THE TSUKUBA HYPERTENSIVE MOUSE (TRANSGENIC MOUSE CARRYING HUMAN GENESFOR BOTH RENIN AND ANGIOTENSINOGEN) AS A MODEL OF HUMAN-MALIGNANT HYPERTENSION - DEVELOPMENT OF LESIONS AND MORPHOMETRIC ANALYSIS

The renin-angiotensin system has a pivotal role in hypertension. The T sukuba hypertensive mouse (THM; a transgenic mouse carrying human gene s for both renin and angiotensinogen) was generated to allow further e xamination of the renin-angiotensin system in a variety of pathologic conditions. We evaluated the development of renal lesions in these mic e and in controls by morphometric, immunohistochemical and ultrastruct ural methods. Blood pressure was significantly higher in THM than in c ontrol mice; 1 year after birth, it was approximately 40 mmHg higher. The kidney-to-body weight ratio was also higher in THM than in control . Morphometrical analysis revealed that the glomerular sclerosis index was significantly elevated in THM with 10% of the glomeruli sclerotic at 18 months. The grade of vascular lesion and the frequency of fibro noid arteritis of the kidney exhibited the same tendency as the glomer ular sclerosis index. Murine renin was located exclusively in the juxt aglomerular apparatus, whereas human renin was expressed not only in t he juxtaglomerular apparatus, but also in periarteriolar smooth muscle cells and in mesangial and epithelial cells of the glomeruli. Light a nd electron microscopy revealed significant fibrinoid arteritis of the kidney in THM and also ''onion skinning'', both pathognomonic for mal ignant nephrosclerosis. THM may be an excellent model of human maligna nt hypertension.