Molecular mechanisms of renal injury

描述(申请人提供)：肾小管间质纤维化是终末期肾脏疾病发展的不良预后指标和常见的最终途径，无论其根本原因如何，最终导致肾组织破坏和不可逆转的肾功能丧失。随着新诊断的慢性肾脏疾病和终末期肾病患者的发病率上升，深入了解潜在机制并确定新的分子靶点以控制肾脏纤维化是开发新疗法以扭转这一令人不安的趋势的基础。肾小管周围毛细血管丢失是进展性肾脏疾病的标志，其结果是血流减少，从而限制了对肾脏的氧气输送，导致慢性肾小管间质缺氧。细胞对低氧适应的关键介质是低氧诱导因子(HIF)-1和-2，它们是碱性-螺旋-环-螺旋转录因子，主要以调节血管重塑、红细胞生成和能量代谢而闻名。在这里，我们假设低氧是肾脏疾病发生和发展的早期和起始事件，HIF信号的激活促进了上皮向间充质转化(EMT)和肾脏纤维化的形成。由于肾脏HIF-1和HIF-2的生物学功能似乎依赖于细胞类型，我们建议进行以下研究：a)在体内特定细胞类型的背景下，研究单独的HIF转录因子在进展性肾脏疾病发病机制中的作用；b)旨在鉴定相关的HIF调控基因和信号通路。具体地说，我们提出的研究包括：a)进行性肾病动物模型结合Cre-loxP介导的重组以实现HIF-1a和HIF-2a的细胞类型特异性失活，b)检测特定的HIF靶基因及其在体内和体外EMT和纤维化形成中的作用的研究，c)基因调控研究，d)利用最先进的基因表达和启动子阵列来确定相关的HIF靶基因的研究。总体而言，这笔赠款旨在建立一个研究计划，调查HIF激活对肾脏疾病发展和进展中至关重要的基因和信号网络表达的影响。拟议的研究将具有直接的临床意义，因为它们强烈鼓励旨在改善肾脏氧输送和消耗之间的平衡的治疗，以阻止肾脏纤维化的进展。公共卫生相关性这项拨款调查了低氧环境在慢性肾脏疾病进展中的作用。一个主要的焦点是通过低氧诱导因子(HIF)途径来传递信号。识别和表征由低氧激活的分子通路有可能为阻止肾脏瘢痕形成的新的治疗方法提供基础。

DESCRIPTION (provided by applicant): Tubulointerstitial fibrosis is a poor prognostic indicator and common final pathway in the development of end-stage renal disease irrespective of the underlying cause, ultimately leading to the destruction of renal tissue and irreversible loss of renal function. As the incidence of patients with newly diagnosed chronic kidney disease and ESRD is rising, sophisticated understanding of underlying mechanisms and identification of new molecular targets to control renal fibrogenesis is fundamental in the development of new therapies to reverse this disturbing trend. Peri-tubular capillary loss is a hallmark of progressive renal disease and results in reduced blood flow that limits oxygen delivery to the kidney leading to chronic tubulointerstitial hypoxia. Key mediators of cellular adaptation to hypoxia are Hypoxia-Inducible-Factor (HIF)-1 and -2, basic-helix-loop- helix transcription factors, mostly known for their ability to regulate vascular remodeling, erythropoiesis, and energy metabolism. Here we hypothesize that hypoxia represents an early and initiating event in the development and progression of kidney disease, and that activation of HIF signaling promotes epithelial to mesenchymal transition (EMT) and renal fibrogenesis. Because the biological functions of renal HIF-1 and HIF-2 appear to be cell-type dependent, we propose studies, which a) investigate the role of individual HIF transcription factors in the pathogenesis of progressive renal disease in a cell-type specific context in vivo and b) are aimed at the identification of relevant HIF regulated genes and signaling pathways. Specifically we propose studies, which include: a) animal models of progressive renal disease in conjunction with Cre-loxP mediated recombination to achieve cell-type specific inactivation of HIF-1a and HIF-2a, b) studies that examine specific HIF target genes and their role in EMT and fibrogenesis in vitro and in vivo, c) gene regulatory studies, and d) studies utilizing state of the art gene expression and promoter arrays to identify relevant HIF target genes. Overall, this grant aims at establishing a research program, which investigates the effects of HIF activation on the expression of genes and signaling networks that are critical in the development and progression of renal disease. The proposed studies will have immediate clinical implications as they strongly encourage therapies that aim at improving the balance between renal oxygen delivery and consumption to halt the progression of renal fibrosis. PUBLIC HEALTH RELEVANCE This grant investigates the role of a low oxygen environment in the progression of chronic kidney disease. A main focus is on signaling through the Hypoxia-Inducible Factor (HIF) pathway. Identification and characterization of molecular pathways that are activated by hypoxia has the potential to provide the basis for new therapeutic approaches to halt the progression of renal scarring.