Spatial transcriptomics reveals the cellular neighborhood of erythropoietin-producing cells in the mouse kidney

The main source of circulating erythropoietin (Epo) in the adult are kidney Norn cells. To shed new lights on the mechanisms governing Epo production, we combined spatial transcriptomics, mRNA-FISH and sequential immunofluorescence, enabling the identification of the direct neighborhood of active REP cells. While in the hypoxic mouse kidney REP cells are closest to proximal tubule (PT) segments (S) S1 to S2/3 and endothelial cells, Epo is re-induced by HIF-stabilizers in damaged kidneys in REP cells in the vicinity of injured PT (but normal endothelial) cells. All tissues analyzed in this work were derived from re-used frozen kidneys originally reported by Dahl et al. Acta Physiol. (Oxf.) 234, e13768. Hypoxic stimulation by exposure to 0.1% CO for 4 hours, unilateral ureteral obstruction (UUO) for 7 days, and the treatment with FG-4592/roxadustat for 90 minutes were described therein.