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成本的疾病结局，与其他不良结局相比，其患病率正在增加。肾损伤及其进展为终末期肾病（ESRD）的发病机制涉及肾氧化应激的产生和导致的组织损伤。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转变。此外，由于多种基因和蛋白质参与自由基的产生和对自由基损伤的防御，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与氧化性肾损伤易感性相关的遗传性高血压动物模型中肾脏基因表达的进行性变化，产生了两个重要的观察结果：第一，肾损伤的出现是通过参与反应性自由基清除的许多基因的明确和协调的下调来预测的;第二，这种协调的功能变化模式似乎是由一个单一的转录因子调节，该转录因子在肾脏中大量表达：肝细胞核因子1，HNF 1。在本研究中，我们将扩展我们的基因阵列和生物信息学方法，通过靶向HNF 1在体外和体内的表达，开发支持高血压肾损伤机制的直接证据。我们将研究肾脏免疫细胞浸润在高血压肾损伤中的作用，其中活化的免疫细胞可能释放在HNF 1转录协调基因表达产生氧化还原应激中起关键作用的细胞因子。我们将调查是否增加盐摄入量的肾损伤的增强是由于HNF 1转录调控介导的氧化应激增加。最后，我们将讨论氧化应激在肾损伤遗传易感性中的作用，通过对比其在两个相关的高血压动物模型中的发展，这两个模型对肾损伤的遗传易感性不同。

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.