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脏损伤是一种疾病后果，与其他不良后果相比，这种疾病的发病率正在增加，造成巨大的健康和经济资源损失。肾脏损伤及其发展为终末期肾病(ESRD)的发病机制涉及肾脏氧化应激的产生和由此导致的组织损伤。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量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变化。此外，由于多个基因和蛋白质同时参与自由基的产生和防御自由基损伤，缺乏这些机制在高血压肾损伤发展过程中变化模式的全面图景。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肾损伤的易感性相关，产生了两个重要的观察结果：第一，肾脏损伤的出现之前，许多参与反应性自由基清除的基因明显和协调地下调；第二，这种协调的功能变化模式似乎受到单一转录因子的调节，该转录因子在肾脏中大量表达：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，通过靶向HNF1在体外和体内的表达来发展支持高血压肾损害这一机制的直接证据。我们将研究肾脏免疫细胞在高血压肾损伤中的作用，在高血压肾损伤中，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。我们将调查盐摄入量增加对肾脏损伤的增强是否归因于HNF1转录调控介导的氧化应激增加。最后，我们将通过比较氧化应激在肾脏损伤遗传易感性不同的两种相关高血压动物模型中的发展，来说明氧化应激在肾脏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.