Renal thrombotic microangiopathy in a genetic model of hypertension in mice.
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(omega)-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.
Sethi
Sanjeev
S
Department of Pathology, Mayo Clinic, 200 1st Street S.W., Rochester, MN 55905, USA. sethi.sanjeev@mayo.edu
Iida
Shinichiro
S
Sigmund
Curt D
CD
Heistad
Donald D
DD
D000809:Angiotensins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D007668:Kidney / Q000098:blood supply* / Q000473:pathology* / Q000502:physiology; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D008822:Mice, Transgenic; D008833:Microcirculation; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D012079:Renal Circulation; D012083:Renin / Q000235:genetics / Q000378:metabolism; D012982:Sodium, Dietary
D000809:Angiotensins; D004791:Enzyme Inhibitors; D012982:Sodium, Dietary; D012083:Renin; D019331:NG-Nitroarginine Methyl Ester