HNF1 transcriptional control of renal oxidative stress

描述（由申请人提供）：与高血压、糖尿病和代谢综合征相关的肾损伤是一种对健康和经济资源造成巨大损失的疾病，与其他不良后果相比，这种疾病的发病率正在上升。肾损伤的发病机制及其进展到终末期肾病（ESRD）涉及肾脏氧化应激的产生和由此引起的组织损伤。不幸的是，人们对这种氧化应激的起源知之甚少。目前尚不清楚氧化自由基产生的增加与自由基清除的减少在多大程度上有助于氧化还原平衡的改变。此外，由于多种基因和蛋白质既参与自由基的产生，又参与自由基损伤的防御，因此缺乏对高血压肾损伤发展过程中这些机制变化模式的全面了解。我们最近的工作分析了遗传性高血压动物模型中肾脏基因表达的进行性变化与氧化性肾损伤的易感性的关系，产生了两个重要的观察结果：首先，肾损伤的出现是由许多参与反应性自由基清除的基因的明确和协调的下调引起的；其次，这种协调的功能变化模式似乎是由一个在肾脏中大量表达的转录因子调节的：肝细胞核因子1，HNF1。在目前的研究中，我们将扩展我们的基因阵列和生物信息学方法，通过在体外和体内靶向HNF1表达来寻找支持高血压肾损伤机制的直接证据。我们将研究肾免疫细胞浸润在高血压肾损伤中的作用，其中激活的免疫细胞可能释放在HNF1转录协调基因表达中发挥关键作用的细胞因子，从而产生氧化还原应激。我们将研究盐摄入量增加对肾损伤的增强是否可归因于HNF1转录控制介导的氧化应激增加。最后，我们将通过对比氧化应激在两种相关的高血压动物模型中对肾损伤的遗传易感性的发展，来解决氧化应激在肾损伤遗传易感性中的作用。

DESCRIPTION (provided by applicant): Renal injury associated with hypertension, diabetes and the metabolic syndrome is a disease outcome of enormous cost to health and economic resources that, in contrast to other adverse outcomes, is increasing in prevalence. The pathogenesis of renal injury and its progression to end stage renal disease (ESRD) involves the generation of renal oxidative stress and resulting tissue injury. Unfortunately, little is known about the origin of this oxidative stress. It is unclear to what extent increased oxidative free radical production versus reduced free-radical scavenging contribute to the shift in redox balance. Furthermore, since multiple genes and proteins are involved both in radical production and in defense against radical injury, a comprehensive picture of the pattern of changes in these mechanisms as hypertensive renal injury develops is lacking. Our recent work analyzing the progressive changes in renal gene expression in an animal model of heritable hypertension in association with susceptibility to oxidative renal injury has generated two important observations: first, the emergence of renal injury is preceeded by a clear and coordinated down-regulation of many genes involved in reactive radical scavenging; second, this coordinated pattern of functional change appears to be regulated by a single transcription factor abundantly expressed in kidney: hepatocyte nuclear factor 1, HNF1. In the present studies, we will extend our gene array and bioinformatics methods to develop direct evidence supporting this mechanism of renal injury in hypertension by targeting HNF1 expression in vitro and in vivo. We will investigate the role of renal immune cell infiltration in hypertensive renal injury in which activated immune cells may release cytokines that play a key role in HNF1 transcriptional coordination of gene expression to produce redox stress. We will investigate whether the enhancement of renal injury by increased salt intake is attributable to increased oxidative stress mediated by HNF1 transcriptional control. Finally, we will address the role of oxidative stress in heritable susceptibility to renal injury by contrasting its development in two related animal models of hypertension differing in their genetic susceptibility to renal injury.