Prolyl-4-hydroxylase domain enzymes and erythropoietin producing mesenchymal stem cell (MSC) like cells in the kidney

促红细胞生成素(EPO)是诱导红细胞生成的关键激素。EPO是在肾脏中以氧依赖的方式产生的，它与缺氧诱导因子(HIF)信号通路联系在一起。病理情况，如慢性肾脏疾病，损害肾脏合成EPO的能力，导致低增殖性贫血。重组促红细胞生成素是目前治疗这种疾病的标准疗法。HIF调节脯氨基-4-羟基酶结构域(PHD)酶的发现，推动了各自的PHD抑制剂(PHI)的开发，并已进入临床试验。原则上，PHI模拟包括EPO产生在内的慢性低氧条件。然而，PHI治疗的长期后果、与生理性低氧相比的不同效果以及这种治疗策略的组织保护潜力几乎还不清楚。在我们的初步工作中，我们发现了一种迄今未被探索的产生EPO的SCA-1+间充质干细胞(MSC)样细胞群，其数量在PHI roxadustat治疗后仅在肾脏中增加。在拟议的项目中，我们的目标是更好地了解PHI诱导的细胞群体在肾脏中内源性EPO的产生以及组织保护。更好地了解SCA-1+细胞群对于进一步开发PHI治疗策略将是重要的。

Erythropoietin (EPO) is the critical hormone for inducing erythropoiesis. EPO is produced in the kidney in an oxygen-dependent manner, which links it to the Hypoxia inducible factor (HIF) signaling pathway. Pathological conditions, such as chronic kidney disease impair the renal ability to synthesize EPO resulting in hypoproliferative anemia. Recombinant EPO is currently the standard of care in this disease. The discovery of the HIF regulating Prolyl-4-hydroxylase domain (PHD) enzymes has pursued the development of respective PHD inhibitors (PHI) that have entered clinical trials. In principle PHI simulate chronic hypoxic conditions including EPO production. However, the long-term consequences, differential effects of PHI treatment compared to physiological hypoxia and tissue protection potential of this treatment strategy are scarcely understood. In our preliminary work we have identified a so far unexplored EPO-producing Sca-1+ mesenchymal stem cell (MSC) like cell population, whose number increased exclusively in the kidney after treatment with the PHI roxadustat. In the proposed project we aim to better understand the PHI-induced cell population for endogenous EPO production in the kidney as well as for tissue protection. A better understanding of the Sca-1+ cell population will be important for the further development of PHI treatment strategies.