Genetics of Renal End Organ Damage in Hypertension

摘要：在美国，终末期肾脏疾病的发病率正以惊人的速度增长，其中高血压和糖尿病是主要原因。目前，有2560万人处于肾脏疾病的早期阶段（1 - 3期），虽然严格控制血压和血糖水平可能会减缓，但并不能阻止这些患者肾功能的进行性下降。因此，了解高血压肾病的遗传基础具有重要意义。在确定家族性肾病（肾病综合征）的遗传原因方面取得了重大进展。然而，没有发现遗传变异与常见形式的肾脏疾病有因果关系。我们的目标是更好地了解在达尔盐敏感(S)大鼠中观察到的高血压性肾脏疾病的遗传基础，它表现出明显的蛋白尿和局灶节段性肾小球硬化（FSGS）。对来自美国的人群进行了蛋白尿和肾损伤的初步遗传分析。研究确定了10个与肾损伤（通过蛋白尿测量）和/或功能相关的基因组区域。在2号染色体上发育的基因菌株表现出明显减少的蛋白尿和FSGS。该提案将评估位于大鼠2号染色体小区域的遗传变异在s大鼠观察到的进行性FSGS和蛋白尿中起重要作用的假设。根据同源菌株分析，致病位点已缩小到<1.2 mb，包含27个基因。然而，跨物种比较、基于近交的SNP分析、综合编码序列和基因表达分析已经令人信服地确定了4个基因，值得进一步研究。本研究的目的是：(1)进行血压和肾脏血流动力学的时间研究，包括肾血流、肾小球毛细血管压力和肾小球通透性；(2)对大鼠2号染色体上狭窄区域的基因进行全面的基因表达、western blot分析、测序和单倍型分析；(3)利用基于细胞和全动物的方法评估已鉴定的等位变异的功能意义。综上所述，本提案将在高血压肾病Dahl s模型中识别和优先考虑与蛋白尿和FSGS相关的基因，并为功能研究、基因验证以及最终在人类人群中进行研究提供基础。

DESCRIPTION (provided by applicant): Abstract There is an alarming increase in the incidence of end-stage renal disease in the Unites States, with hypertension and diabetes being the major cause. Currently, 25.6 million people are in the early phase of kidney disease (stage 1 to 3) and while strict control of blood pressure and glucose levels may slow, it will not prevent the progressive decline of renal function in these patients. Therefore, understanding the genetic basis of hypertension-induced renal disease is of considerable interest. Significant progress has been made to identify the genetic causes of familial forms of renal disease (nephrotic syndrome). However, no genetic variants have been found to be causally linked to common forms of renal disease. It is our goal to develop a better understanding of the genetic basis of hypertension-induced renal disease observed in the Dahl salt- sensitive (S) rat, which exhibits significant proteinuria and focal segmental glomerulosclerosis (FSGS). An initial genetic analysis for proteinuria and renal injury was performed using a population derived from the S. The study identified ten genomic regions linked to renal damage (measured by proteinuria) and/or function. A congenic strain developed on chromosome 2 exhibited significantly less proteinuria and FSGS. This proposal will evaluate the hypothesis that genetic variant(s) located to a small region on rat chromosome 2 play a significant role in the progressive FSGS and proteinuria observed in the S rat. Based on congenic strain analysis, the causative locus has been narrowed to <1.2 Mbs containing 27 genes. However, cross-species comparative, inbred-based SNP analysis, comprehensive coding sequence and gene expression analysis has convincingly identified 4 genes for further study. The aims of the proposed study are: (1) to perform temporal studies of blood pressure and renal hemodynamics, including renal blood flow, glomerular capillary pressure, and glomerular permeability in the S and small congenic strain; (2) to perform comprehensive gene expression, western blot analysis, sequencing, and haplotype analysis for genes narrowed to the small region on rat chromosome 2; and (3) to evaluate the functional significance of identified allelic variants using cell- based and whole-animal approaches. In summary, this proposal will identify and prioritize gene(s) linked to proteinuria and FSGS in the Dahl S model of hypertension-induced renal disease and provide a basis for functional studies, gene validation, and eventually study in human-based populations.