Renal pathology in hemizygous sickle cell mice
Renal pathology in hemizygous sickle cell mice
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DOI：
10.1080/019262302753559597
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发表时间：
2002-03-01
影响因子：
1.5
通讯作者：
Buzard, GS
中科院分区：
文献类型：
--
作者：
Diwan, BA;Gladwin, MT;Buzard, GS
已经开发出转基因小鼠，它们只表达人类镰状细胞β血红蛋白，并且具有镰状细胞病患者的主要病理特征。这些小鼠提供了一个独特的机会来研究这种疾病的基本机制，并设计新的策略来纠正相关的遗传缺陷。我们发现，在只表达成年人类α -珠蛋白和镰状β -珠蛋白的雄性（纯合子SS小鼠）与含有这些转基因和一个小鼠β -珠蛋白基因拷贝的雌性（半合子SS小鼠）交配时，产生的半合子后代比纯合子小鼠（不携带小鼠β -珠蛋白基因）的预期数量要多。这些半合子小鼠，表达人类α和镰状β (s)转基因与小鼠β(+/-)结合，用于我们肾脏病理的初步研究。对照组（129/Sv）小鼠未发现肾脏病变，而约50%的半合子SS小鼠出现轻至重度肾脏病变，包括肾小球肾炎、囊性非典型增生性小管和一般肾病。一些半合子小鼠的肾脏正常或表现出轻微的肾病，而那些易感表型的小鼠则出现了轻度至更严重的肾脏病变。受影响表型较重的半合子小鼠肾小管上皮诱导型一氧化氮合酶的表达增加，3-硝基酪氨酸在近距离增加。与正常对照小鼠相比，肾皮质间质毛细血管细胞和小管上皮细胞中血管细胞粘附分子-1的免疫染色也较强。我们的半合子SS小鼠肾脏异常的高发生率表明，这些小鼠可能为研究由血流量改变和/或氧输送不足引起的肾病的发病机制提供了合适的模型。
Transgenic mice have been developed that express exclusively human sickle cell beta hemoglobin and have major pathological features found in humans with sickle cell disease. These mice provide a unique opportunity to investigate the fundamental mechanisms of this disease and to design new strategies to correct the associated genetic defect(s). We found that in breeding males expressing only adult human alpha-globin and sickle beta-globin (homozygous SS mice) with females containing these transgenes plus one copy of the mouse beta-globin gene (hemizygous SS mice) greater than expected numbers of hemizygous offspring were produced than homozygous mice (carrying no mouse beta-globin gene). These hemizygous mice, expressing the human alpha and sickle beta(s) transgenes in combination with mouse beta(+/-), were used for our preliminary studies of their renal pathology. No kidney lesions were found in the control (129/Sv) mice, whereas about 50% of the hemizygous SS mice showed mild-to-severe kidney lesions, including glomerulonephritis, cystic atypical hyperplastic tubules, and general nephropathy. Kidneys of some hemizygous mice were normal or showed minimal nephropathy, yet those of the susceptible phenotype developed a mild-to-more-severe form of renal lesions. The tubular epithelium of kidneys of hemizygous mice of the more affected phenotype exhibited increased expression of inducible nitric oxide synthase with an increased 3-nitrotyrosine in close proximity. There was also a stronger immunostaining for vascular cell adhesion molecule-1 in the interstitial capillary cells as well as the tubular epithelial cells of the renal cortex, compared with normal control mice. The occurrence of a high incidence of renal abnormalities in our hemizygous SS mice suggests that these mice may provide a suitable model to study the pathogenesis of nephropathy resulting from altered blood flow and/or insufficient oxygen delivery.