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ORIGINAL RESEARCH ARTICLE

Renal Thrombotic Microangiopathy in a Genetic Model of Hypertension in Mice

Sanjeev Sethi^*,1, Shinichiro Iida, Curt D. Sigmund^, and Donald D. Heistad^,

^* Department of Pathology, Mayo Clinic, Rochester, MN 55905; Departments of Internal Medicine, Physiology and Biophysics, and Pharmacology, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, and VA Medical Center, Iowa City, Iowa 52242

To whom requests for reprints should be addressed at ¹ Department of Pathology, Mayo Clinic, 200 1st Street S.W., Rochester, MN 55905. E-mail: sethi.sanjeev{at}mayo.edu

Our goal was to develop a model of accelerated hypertension with renal microangiopathy. Transgenic mice that are hypertensive because of overexpression of human renin (R⁺ mice) and human angiotensin (A⁺ mice) genes were studied. To increase arterial pressure to levels comparable to those that may be seen in malignant hypertension, high salt was added to the diet and/or the nitric oxide synthase inhibitor, N-nitro-L-arginine methylester (L-NAME), was added to the drinking water. Renal lesions, decline in renal function, and proteinuria developed within 10 weeks in R⁺/A⁺ mice given both L-NAME and a high-salt diet, and within 24 weeks in mice given either L-NAME or a high-salt diet. Renal morphology showed features of severe thrombotic microangiopathy, with extensive vascular and glomerular lesions in all R⁺/A⁺ mice on high salt, L-NAME, or high salt plus L-NAME. Vascular lesions included fibrin thrombi and onion skinning of the vessel walls, whereas glomerular lesions included segmental sclerosis, mesangiolysis, fibrin thrombi within glomerular capillaries, and double-contour formation of glomerular capillary walls. Renal morphology was normal in control mice fed high salt and/or L-NAME. No R⁺/A⁺ mice fed a normal diet developed vascular lesions, whereas a few mice developed mild focal glomerular lesions. In summary, these studies characterize vascular and glomerular lesions in R⁺/A⁺ mice fed high salt, L-NAME, or both high salt and L-NAME, and provide a murine model of malignant hypertension with renal thrombotic microangiopathy.

Key Words: hypertension • renal thrombotic microangiopathy • renin angiotensin • transgenic mice