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

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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.