Cellular and Molecular Mechanisms of Renal Anemia

晚期慢性肾脏病(CKD)和终末期肾病(ESRD)的特点是 疾病肾脏不能产生足够的促红细胞生成素(EPO)来应对缺氧， 一种糖蛋白激素，对生成红细胞是必不可少的，而且还与 有绝对和功能性的铁缺乏。这会导致贫血的发展，这是 晚期慢性肾脏病，通常用重组人促红细胞生成素和静脉铁制剂治疗。 重组促红细胞生成素的使用不仅是晚期糖尿病患者护理的主要成本因素 CKD和ESRD，但也与重大心血管风险有关，促使FDA发布 几个黑匣子警告。虽然重组人促红细胞生成素已经使用了25年以上，但 肾性贫血的发病机制尚不清楚。这项研究项目的长期目标是 了解肾性贫血发病的细胞和分子机制。 肾脏EPO氧依赖调节的一个关键途径是Pro-4-羟基酶(PHD)/ 缺氧诱导因子(HIF)途径。在过去的10年里，我们的实验室和其他实验室已经证明 HIF-2调节肾脏和肝脏EPO的缺氧性诱导。肾性贫血的发病机制是 与肾脏纤维化有复杂的联系，因为血管周围间质细胞和周细胞不仅是细胞 促红细胞生成素在肾脏中的来源，但也能促进产生胶原的肌成纤维细胞。要了解 慢性肾脏病肾脏促红细胞生成素在细胞和分子水平的调节 药理学工具被用来解剖正常肾脏和受损肾脏的PHD/HIF/EPO轴。 根据这笔赠款，我们假设PHD/HIF氧气传感系统与铁结合 反应元件结合蛋白(IRP)在调节EPO-1细胞分化状态中起关键作用。 产生血管周围间质细胞和周细胞。我们认为，异常的HIF-2调节会产生 调节细胞分化和功能的特定信号，因此在发病机制中起关键作用 肾性贫血。我们的研究旨在a)阐明血管周围PHD/HIF-2轴在贫血中的作用 肾脏损伤条件下的发育，b)表征与以下因素相关的分子表型 利用单细胞RNA测序技术生产EPO的细胞和c)在研究 IRp1在基础状态下调节肾间质细胞HIF-2活性和EPO产生中的作用 和肾脏损伤的情况。

Advanced chronic kidney disease (CKD) and end stage renal disease (ESRD) are characterized by the inability of the diseased kidney to respond to hypoxia with adequate production of erythropoietin (EPO), the glycoprotein hormone that is essential for the generation of red blood cells, and is furthermore associated with absolute and functional iron deficiency. This leads to the development of anemia, a clinical hallmark of advanced CKD, which is typically treated with recombinant human EPO and intravenous iron preparations. The use of recombinant EPO not only represents a major cost factor in the care of patients with advanced CKD and ESRD, but also is associated with significant cardiovascular risks prompting the FDA to issue several black box warnings. While recombinant human EPO has been in use for over 25 years, the pathogenesis of renal anemia is poorly understood. The long-term goals of this research project are to understand the cellular and molecular mechanisms that underlie the pathogenesis of renal anemia. A key pathway in the oxygen-dependent regulation of renal EPO is the prolyl-4-hydroxylase (PHD) / hypoxia-inducible factor (HIF) pathway. Over the last 10 years our laboratory and others have demonstrated that HIF-2 regulates the hypoxic induction of EPO in kidney and liver. The pathogenesis of renal anemia is intricately linked to renal fibrogenesis, as perivascular interstitial cells and pericytes are not only the cellular sources of EPO in the kidney but also give rise to collagen-producing myofibroblasts. To understand the regulation of renal EPO production in CKD on a cellular and molecular level unique genetic and pharmacologic tools are used to dissect the PHD/HIF/EPO axis in normal and in injured kidneys. Under this grant we hypothesize that the PHD/HIF oxygen sensing system in conjunction with iron responsive element binding protein (IRP) plays a critical role in regulating the differentiation state of EPO- producing perivascular interstitial cells and pericytes. We propose that abnormal HIF-2 regulation generates specific signals that modulate cell differentiation and function and thus has a crucial role in the pathogenesis of renal anemia. Our studies aim at a) elucidating the role of the perivascular PHD/HIF-2 axis in anemia development under renal injury conditions, b) at characterizing molecular phenotype that associates with EPO-producing cells taking advantage of single cell RNA sequencing technology and c) at investigating the role of IRP1 in the regulation of HIF-2 activity in renal interstitial cells and EPO production under baseline and kidney injury conditions.