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在肾脏中以氧依赖性方式产生，这将其与缺氧诱导因子（HIF）信号传导途径联系起来。病理条件，如慢性肾病损害肾脏合成EPO的能力，导致低增殖性贫血。重组EPO是目前治疗这种疾病的标准。HIF调节脯氨酰-4-羟化酶结构域（PHD）酶的发现已经推动了已经进入临床试验的相应PHD抑制剂（PHI）的开发。原则上，PHI模拟慢性缺氧条件，包括EPO产生。然而，长期的后果，不同的影响PHI治疗相比，生理缺氧和组织保护这种治疗策略的潜力很少被理解。在我们的初步工作中，我们已经鉴定了迄今为止未探索的产生EPO的Sca-1+间充质干细胞（MSC）样细胞群，其数量在用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诱导的细胞群在肾脏中的内源性EPO生产以及组织保护。更好地了解Sca-1+细胞群体对于进一步开发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.