Hypertensive renal disease: susceptibility and resistance in inbred hypertensive rat lines
Hypertensive renal disease: susceptibility and resistance in inbred hypertensive rat lines
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DOI：
10.1097/hjh.0b013e328362f9a5
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发表时间：
2013-10-01
影响因子：
4.9
通讯作者：
Doris, Peter A.
中科院分区：
文献类型：
--
作者：
Braun, Michael C.;Herring, Stacy M.;Doris, Peter A.
背景：自发性高血压大鼠（SHR）品系对高血压终末器官疾病的易感性不同，可能提供疾病遗传风险的信息模型。来自原始SHR-B和SHR-C分支的品系对高血压终末器官疾病具有高度抗性，而来自SHR-A分支的品系被选择用于中风易感性和经历高血压性肾病diseases.Method：在这里，我们描述了在饮食和饮用水中消耗0.3%钠的SHR-A3动物中进行性肾损伤的时间发展。SHR-A3大鼠表现出蛋白尿，肾小球损伤，肾小管间质损伤，肾纤维化，出现在18周龄和progress.Results和结论：SHR-A3动物的死亡率为50%，在40周龄，动物存活到这个年龄，肾功能下降。相比之下，与SHR-A3有87%遗传相同性的SHR-B2基本上受到保护免于肾损伤，并且在这段时间内仅表现出白蛋白尿和肾组织学损伤的中度变化。在40周龄时，肾小球的电子显微镜检查显示SHR-A3中有严重的足细胞消失，但SHR-B2在该年龄的裂膈结构保存良好。在此模型中，对SHR-A3和SHR-B2杂交的F1和F2后代的肾损伤性状进行了测定，以确定肾损伤的遗传度。白蛋白尿、肾小球损伤和肾小管间质损伤的遗传度估计分别为48.9%、66.5%和58.6%。我们评估了F2动物血压和肾损伤指标之间的关系，发现这些变量之间存在一定的相关性，可以解释高达26%的性状变异。使用分布在这两个密切相关的品系之间不同的13%的基因组中的200多个单核苷酸多态性标记进行数量性状基因座（QTL）作图。蛋白尿、肾小管间质损伤和肾纤维化的定位未能确定与疾病易感性相关的位点，提示疾病风险的复杂遗传。我们检测到一个单一的QTL赋予肾小球损伤的易感性，仅限于一个小的单倍型块在染色体14：70- 76 Mb。
Background:Spontaneously hypertensive rat (SHR) lines differ in their susceptibility to hypertensive end-organ disease and may provide an informative model of genetic risk of disease. Lines derived from the original SHR-B and SHR-C clades are highly resistant to hypertensive end-organ disease, whereas lines derived from the SHR-A clade were selected for stroke susceptibility and experience hypertensive renal disease.Method:Here we characterize the temporal development of progressive renal injury in SHR-A3 animals consuming 0.3% sodium in the diet and drinking water. SHR-A3 rats demonstrate albuminuria, glomerular damage, tubulointerstitial injury, and renal fibrosis that emerge at 18 weeks of age and progress.Results and conclusion:Mortality of SHR-A3 animals was 50% at 40 weeks of age, and animals surviving to this age had reduced renal function. In contrast SHR-B2, which are 87% genetically identical to SHR-A3, are substantially protected from renal injury and demonstrate only moderate changes in albuminuria and renal histological injury over this time period. At 40 weeks of age, electron microscopy of the renal glomerulus revealed severe podocyte effacement in SHR-A3, but slit diaphragm architecture in SHR-B2 at this age was well preserved. Renal injury traits in the F1 and F2 progeny of an intercross between SHR-A3 and SHR-B2 were measured to determine heritability of renal injury in this model. Heritability of albuminuria, glomerular injury, and tubulointerstitial injury were estimated at 48.9, 66.5 and 58.6%, respectively. We assessed the relationship between blood pressure and renal injury measures in the F2 animals and found some correlation between these variables that explain up to 26% of the trait variation. Quantitative trait locus (QTL) mapping was performed using over 200 single nucleotide polymorphism markers distributed across the 13% of the genome that differs between these two closely related lines. Mapping of albuminuria, tubulointerstitial injury, and renal fibrosis failed to identify loci linked with disease susceptibility, suggesting a complex inheritance of disease risk. We detected a single QTL conferring susceptibility to glomerular injury that was confined to a small haplotype block at chromosome 14:70-76Mb.