Figure 1.

Mechanisms of hypoxia-inducible erythropoietin (EPO) production in renal EPO-producing (REP) cells and failure of EPO production in fibrotic kidney. (A) A schema of REP cell localization in the interstitia between renal tubules. REP cells directly associate with capillaries (Souma et al., 2016). (B) REP cells (red) distributed to the outer medulla (m) and cortex (c) of a normal healthy kidney (left) are expanded in a fibrotic kidney (right) of a genetically modified mouse line specifically expressing tdTomato fluorescence in REP cells (Yamazaki et al., 2013). (C) Distributions of ON-REP (green), OFF-REP (white), early myofibroblast (eMF)-REP (yellow), and progressive MF (pMF)-REP (gray) in normal kidneys and fibrotic kidneys. Note that a small fraction of REP cells produce EPO even under hypoxic conditions (left). (D) EPO-gene regulation by the PHD2-HIF2α pathway in REP cells and MF-REP cells. In eMF-REP cells (reversibly transformed REP cells), PHD2 over-activation results in inactivation of EPO-gene transcription. Therefore, PHD inhibitors may induce EPO production. Because the genes for EPO and HIF2α are epigenetically inactivated due to DNA methylation (Me) in pMF-REP cells (irreversibly transformed REP cells), PHD inhibitors are ineffective. (E) Molecular mechanism of hypoxia-inducible transcriptional regulation. HIFα proteins are always synthesized and degraded by the ubiquitin (Ub)-proteasome pathway via PHD-mediated hydroxylation (OH) in oxygen-replete cells. In hypoxic cells, PHD is inactivated, and HIFα proteins are stabilized. In some HIF-target gene promoters, HIFα/β complexes mediate the disassembly of nucleosome structures to form nucleosome-free regions under hypoxic conditions.