Cellular and Molecular Mechanisms of Renal Anemia

描述（由申请人提供）： 我们的长期目标是了解肾性贫血的发病机制，并开发新的和安全的治疗方法。贫血是晚期慢性肾病（CKD）的典型表现，并且是由于患病肾脏产生足够量的促红细胞生成素（EPO）的能力降低所致，促红细胞生成素是红细胞生成所必需的糖蛋白激素。与CKD或终末期肾病（ESRD）相关的贫血通常用重组EPO治疗。重组EPO的使用不仅代表了晚期CKD和ESRD患者护理的主要成本因素，而且还引起了重大的心血管安全性问题，这促使FDA发布了几个黑盒警告。虽然给予肾脏患者重组EPO已经成为肾脏病学支持性治疗的标志超过20年，但令人惊讶的是，对肾性贫血发病机制的分子机制知之甚少。调节肾EPO产生的关键途径是缺氧诱导因子（HIF）途径。虽然EPO的低氧诱导作为低氧基因调控的范例，但在肾损伤条件下肾EPO合成的调控在细胞和分子水平上都不完全理解。在过去的5年里，我们的实验室和其他小组已经证明，HIF-2调节肾脏和肝脏中EPO的缺氧诱导，并且HIF途径可以被靶向治疗贫血患者。为了了解细胞和分子水平上肾EPO产生的调节，我们已经开始使用遗传学和药理学方法来解剖正常和受损肾脏中的HIF/EPO轴。根据这项研究，我们假设HIF-2通过调节肾间质细胞的可塑性来控制肾EPO的产生。我们使用基因工程小鼠来a）确定肾脏中具有EPO产生能力的细胞类型，B）确定它们在EPO产生中的作用。 c）表征三种主要HIF脯氨酰-羟化酶在肾间质缺氧调节中的作用 反应和d）在肾损伤条件下检查HIF-2功能。

DESCRIPTION (provided by applicant): Our long-term goal is to understand the pathogenesis of renal anemia and to develop new and safe therapies for its treatment. Anemia is a classic manifestation of advanced chronic kidney disease (CKD) and results from the diminished ability of the diseased kidney to produce adequate amounts of erythropoietin (EPO), the glycoprotein hormone that is essential for red blood production. Anemia associated with CKD or end stage renal disease (ESRD) is typically treated with recombinant EPO. The use of recombinant EPO not only represents a major cost factor in the care of patients with advanced CKD and ESRD, but also has raised significant cardiovascular safety concerns, which prompted the FDA to issue several black box warnings. While the administration of recombinant EPO to renal patients has been a hallmark of supportive care in Nephrology for more than 20 years, the molecular mechanisms that underlie the pathogenesis of renal anemia are surprisingly poorly understood. A key pathway in the regulation of renal EPO production is the hypoxia-inducible factor (HIF) pathway. Although the hypoxic induction of EPO serves as a paradigm for hypoxic gene regulation, the regulation of renal EPO synthesis under renal injury conditions is incompletely understood on both, the cellular and the molecular level. Over the last 5 years our laboratory and other groups have demonstrated that HIF-2 regulates the hypoxic induction of EPO in the kidney and liver, and that the HIF pathway can be pharmacologically targeted to treat patients with anemia. To understand the regulation of renal EPO production on a cellular and molecular level we have begun to use genetic and pharmacologic approaches to dissect the HIF/EPO axis in normal and in injured kidneys. Under this grant, we hypothesize that HIF-2 controls renal EPO production by regulating renal interstitial cell plasticity. We use genetically engineered mice to a) define the cell types in the kidney that have EPO-producing ability, b) to determine their contribution in the regulation of erythropoiesis at baseline and under hypoxic stress conditions, c) to characterize the role of the three major HIF prolyl-hydroxylases in the regulation of renal interstitial hypoxia responses and d) to examine HIF-2 function under renal injury conditions.