Yagil Chana, Sapojnikov Marina, Wechsler Alexander, Korol Abraham, Yagil Yoram
Laboratory for Molecular Medicine, Israeli Rat Genome Center, Faculty of Health Sciences, Ben-Gurion University, Barzilai Medical Center Campus, Ashkelon, Israel.
Physiol Genomics. 2006 Mar 13;25(1):121-33. doi: 10.1152/physiolgenomics.00235.2005. Epub 2006 Jan 3.
The pathophysiology underlying proteinuria remains incompletely understood and warrants further research. We currently initiated the investigation of the genetic basis of proteinuria in the Sabra rat, a model of salt susceptibility that we showed previously to be also a model of spontaneous proteinuria that is unrelated to salt loading or development of hypertension. We applied the total genome scan strategy in 75 F2 male animals derived from a cross between SBH/y, which are prone to develop proteinuria, and SBN/y, which are relatively resistant to the development of proteinuria. Animals were subjected to uninephrectomy (UNx) to accelerate the development of proteinuria and were provided chow with a low salt content, thus avoiding the development of hypertension. Urinary protein excretion was monitored before UNx and monthly thereafter for 8 mo. The genotype of F2 was determined with microsatellite markers. The data were analyzed for cosegregation by ANOVA and for genetic linkage with a novel multifaceted statistical genetic paradigm. We detected three proteinuria-related quantitative trait loci (QTL) that were associated with the salt sensitivity (H) alleles from SBH/y: SUP2, SUP17, and SUP20 on rat chromosomes (Chr) 2, 17, and 20. We detected an additional QTL on Chr 3, SUP3, that was associated with the salt resistance (N) alleles from SBN/y. A temporal effect was noted: QTL SUP2 and SUP17 surfaced at months 7-8, QTL SUP20 at months 6-8, and QTL SUP3 at months 5-6. The QTL emerging from this study lead us a step closer to identifying the genes associated with and elucidating the pathophysiology of proteinuria.
蛋白尿背后的病理生理学机制仍未完全明了，值得进一步研究。我们目前已着手对Sabra大鼠蛋白尿的遗传基础展开研究，该大鼠是盐敏感性模型，我们之前已证明它也是自发性蛋白尿模型，与盐负荷或高血压的发展无关。我们在75只F2雄性动物中应用了全基因组扫描策略，这些动物源自易发生蛋白尿的SBH/y和对蛋白尿发展相对有抗性的SBN/y之间的杂交。动物接受单侧肾切除术（UNx）以加速蛋白尿的发展，并给予低盐含量的食物，从而避免高血压的发生。在UNx前及之后每月监测8个月的尿蛋白排泄情况。用微卫星标记确定F2的基因型。通过方差分析对数据进行共分离分析，并采用一种新的多方面统计遗传范式进行遗传连锁分析。我们检测到三个与蛋白尿相关的数量性状基因座（QTL），它们与来自SBH/y的盐敏感性（H）等位基因相关：大鼠染色体（Chr）2、17和20上的SUP2、SUP17和SUP20。我们在Chr 3上检测到另一个QTL，即SUP3，它与来自SBN/y的盐抗性（N）等位基因相关。注意到一种时间效应：QTL SUP2和SUP17在第7 - 8个月出现，QTL SUP20在第6 - 8个月出现，QTL SUP3在第5 - 6个月出现。本研究中出现的QTL使我们在识别与蛋白尿相关的基因和阐明其病理生理学方面又迈进了一步。
