Hypertensive Renal Injury

描述(申请人提供)：超过40万美国人患有终末期肾病(ESRD)，需要透析或肾移植才能存活。在过去的十年中，美国人口中的ESRD人数翻了一番，这一增长是由糖尿病和高血压推动的。ESRD与非常高的死亡率相关，最常见的是心血管疾病(CVD)，而慢性肾损伤患者患CVD的风险增加意味着他们死于CVD的可能性比进展为ESRD的可能性要大得多。患有高血压和/或糖尿病的人患ESRD的风险有很大的差异。这种风险变化的主要决定因素是遗传易感性，它有助于增强高血压和糖尿病造成肾脏损伤的能力。建议的研究集中在一种合并高血压、胰岛素抵抗和血脂异常的肾损伤动物模型--自发性高血压大鼠(SHR)。这个模型概括了高血压和糖尿病患者对肾脏损伤的遗传易感性的作用：SHR-A3系获得高血压肾损伤，而其他高血压SHR系抵抗高血压肾损伤。这些不同的SHR系为鉴定肾脏损伤易感性的机制和基因提供了有价值的手段。我们最近在我们的损伤易感(SHR-A3)和抗性(SHRB2)系中定义了一组高密度的单核苷酸多态(SNP)标记，从而能够高分辨率地绘制控制肾损伤易感性的基因座图谱，从而使拟议的研究成为可能。我们建议使用这些标记来定位这些亲本系的杂交，以识别伤害易感基因座。我们的作图研究结论将通过培育相互同源的菌株来验证，这些菌株固定了易受伤害的SHR-A3和抗伤害的SHR-B2株系的伤害抗性和易感等位基因。最后，我们发现了肾脏氧化还原应激在SHR-A3肾损伤发生中的作用，并确定了导致这种氧化还原应激的转录程序。这提供了一个机会来改进我们的遗传图谱研究，细化到所映射的基因座中特定基因的水平。我们在SHR-A3中阐明的与肾脏氧化还原应激转录途径功能相关的基因将被选择性地重新测序，以确定驱动肾脏损伤途径的特定基因变体。公共卫生相关性糖尿病和高血压引起的肾脏损伤需要超过40万美国人接受肾脏透析治疗才能存活。遗传在肾脏损伤的风险中起着重要作用。在糖尿病和高血压患者中，进展性肾脏疾病的最大风险是在亲属中发生这种疾病。在拟议的研究中，我们将使用这种综合征的大鼠模型来绘制染色体区域的基因图谱，这些区域含有导致肾脏损伤的基因。通过揭示导致老鼠这种损伤的基因，以及这些基因是如何造成这种损伤的，我们将为了解人类疾病以及设想和测试新的治疗方法提供宝贵的新机会。

DESCRIPTION (provided by applicant): Over 400,000 Americans have end-stage renal disease (ESRD) requiring dialysis or kidney transplant for survival. ESRD in the US population doubled in the last decade and this increase is driven by diabetes and hypertension. ESRD is associated with very high rates of mortality, most frequently from cardiovascular disease (CVD), and the heightened risk of CVD in individuals with chronic renal injury means that they are much more likely to die of CVD than to progress to ESRD. There is great variation in risk for ESRD among individuals who have hypertension and/or diabetes. The major determinant of this variation in risk is genetic susceptibility that serves to enhance the capacity of hypertension and diabetes to generate renal injury. The proposed studies focus on an animal model of renal injury with concurrent hypertension, insulin resistance and dyslipidemia, the spontaneously hypertensive rat (SHR). This model recapitulates the role of genetic susceptibility to renal injury in hypertensive and diabetic patients: the SHR-A3 line acquires hypertensive renal injury, while other hypertensive SHR lines resist it. These contrasting SHR lines offer a valuable means to identify the mechanism of and the genes contributing to susceptibility to renal injury. The proposed studies are made possible by our recent progress in defining a set of high density, single nucleotide polymorphism (SNP) markers in our injury-prone (SHR-A3) and resistant (SHRB2) lines that allow high resolution genetic mapping of loci controlling susceptibility to renal injury. We propose here to use these markers to map an intercross of these parental lines that will identify injury susceptibility loci. The conclusions of our mapping study will be tested and verified by breeding reciprocal congenic strains that fix injury resistance and susceptibility alleles in the injury-prone SHR-A3 and the injury-resistant SHR-B2 lines. Finally, we have uncovered the role of renal redox stress in the generation of renal injury in SHR-A3 and identified a transcriptional program that leads to this redox stress. This provides an opportunity to refine our genetic mapping studies down to the level of specific genes within the mapped loci. Genes that are functionally correlated to the transcriptional pathway of renal redox stress that we have elucidated in SHR-A3 will be targeted for selective resequencing to identify specific gene variants that drive the renal injury pathway. PUBLIC HEALTH RELEVANCE Kidney injury caused by diabetes and high blood pressure requires that more than 400,000 Americans be treated by kidney dialysis in order to survive. Heredity plays a major role in risk of kidney injury. Among diabetic and high blood pressure patients, the largest risk of progressive kidney disease is the occurrence of this disease in a relative. In the proposed studies we will use a rat model of this syndrome to genetically map chromosomal regions harboring genes that create risk of kidney injury. By uncovering the genes that cause this injury in rats and how this injury is created by these genes we will open up valuable new opportunities to understand the disease in people and to envision and test new treatments.