Hypertensive Renal Injury

描述（由申请人提供）：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生存。在过去十年中，美国人口中的ESRD翻了一番，这种增长是由糖尿病和高血压驱动的。ESRD与非常高的死亡率相关，最常见的是心血管疾病（CVD），慢性肾损伤患者的CVD风险升高意味着他们更有可能死于CVD而不是进展为ESRD。在患有高血压和/或糖尿病的个体中，ESRD的风险存在很大差异。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产生肾损伤的能力。本研究拟以自发性高血压大鼠（SHR）作为肾损伤伴高血压、胰岛素抵抗和血脂异常的动物模型。该模型概括了高血压和糖尿病患者肾损伤遗传易感性的作用：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。这些对比SHR系提供了一种有价值的手段，以确定肾损伤的机制和基因的易感性。我们最近在我们的易损伤（SHR-A3）和耐药（SHRB 2）系中定义了一组高密度单核苷酸多态性（SNP）标记，这些标记允许控制肾损伤易感性的基因座的高分辨率遗传作图，这使得拟议的研究成为可能。我们建议在这里使用这些标记来映射这些亲本系的互交，以确定损伤易感性位点。我们的定位研究的结论将通过培育相互同源的菌株，固定损伤的易感性SHR-A3和损伤抗性SHR-B2系的损伤抗性和易感性等位基因进行检验和验证。最后，我们揭示了肾脏氧化还原应激在SHR-A3肾损伤中的作用，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，以完善我们的遗传作图研究下降到特定基因的水平在映射的基因座。我们在SHR-A3中阐明的与肾氧化还原应激的转录途径功能相关的基因将被靶向用于选择性重测序，以鉴定驱动肾损伤途径的特定基因变体。由糖尿病和高血压引起的肾损伤需要40多万美国人通过肾透析治疗才能生存。遗传在肾损伤风险中起主要作用。在糖尿病和高血压患者中，进行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遗传定位染色体区域，这些区域含有产生肾损伤风险的基因。通过揭示导致大鼠这种损伤的基因以及这些基因是如何造成这种损伤的，我们将开辟宝贵的新机会，以了解人类的疾病，并设想和测试新的治疗方法。

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.