Churchill P C, Churchill M C, Bidani A K, Griffin K A, Picken M, Pravenec M, Kren V, St Lezin E, Wang J M, Wang N, Kurtz T W
Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
J Clin Invest. 1997 Sep 15;100(6):1373-82. doi: 10.1172/JCI119657.
To test the hypothesis that genetic factors can determine susceptibility to hypertension-induced renal damage, we derived an experimental animal model in which two genetically different yet histocompatible kidneys are chronically and simultaneously exposed to the same blood pressure profile and metabolic environment within the same host. Kidneys from normotensive Brown Norway rats were transplanted into unilaterally nephrectomized spontaneously hypertensive rats (SHR-RT1.N strain) that harbor the major histocompatibility complex of the Brown Norway strain. 25 d after the induction of severe hypertension with deoxycorticosterone acetate and salt, proteinuria, impaired glomerular filtration rate, and extensive vascular and glomerular injury were observed in the Brown Norway donor kidneys, but not in the SHR-RT1.N kidneys. Control experiments demonstrated that the strain differences in kidney damage could not be attributed to effects of transplantation-induced renal injury, immunologic rejection phenomena, or preexisting strain differences in blood pressure. These studies (a) demonstrate that the kidney of the normotensive Brown Norway rat is inherently much more susceptible to hypertension-induced damage than is the kidney of the spontaneously hypertensive rat, and (b) establish the feasibility of using organ-specific genome transplants to map genes expressed in the kidney that determine susceptibility to hypertension-induced renal injury in the rat.
为了验证遗传因素可决定高血压所致肾损伤易感性这一假说，我们构建了一种实验动物模型，在同一宿主内，将两个基因不同但组织相容性相同的肾脏长期同时暴露于相同的血压状况和代谢环境中。将正常血压的挪威棕鼠的肾脏移植到单侧肾切除的自发性高血压大鼠（SHR-RT1.N品系）体内，该自发性高血压大鼠携有挪威棕鼠品系的主要组织相容性复合体。在用醋酸脱氧皮质酮和盐诱导严重高血压25天后，在挪威棕鼠供体肾脏中观察到蛋白尿、肾小球滤过率受损以及广泛的血管和肾小球损伤，但在SHR-RT1.N肾脏中未观察到。对照实验表明，肾脏损伤的品系差异不能归因于移植诱导的肾损伤、免疫排斥现象或既往存在的血压品系差异。这些研究（a）表明，正常血压的挪威棕鼠的肾脏比自发性高血压大鼠的肾脏在本质上对高血压诱导的损伤更敏感，并且（b）确立了使用器官特异性基因组移植来定位大鼠肾脏中表达的决定对高血压诱导的肾损伤易感性的基因的可行性。
