Erythropoietin Synthesis in Renal Myofibroblasts Is Restored by Activation of Hypoxia Signaling.


Journal Article

Erythropoietin (Epo) is produced by renal Epo-producing cells (REPs) in a hypoxia-inducible manner. The conversion of REPs into myofibroblasts and coincident loss of Epo-producing ability are the major cause of renal fibrosis and anemia. However, the hypoxic response of these transformed myofibroblasts remains unclear. Here, we used complementary in vivo transgenic and live imaging approaches to better understand the importance of hypoxia signaling in Epo production. Live imaging of REPs in transgenic mice expressing green fluorescent protein from a modified Epo-gene locus revealed that healthy REPs tightly associated with endothelium by wrapping processes around capillaries. However, this association was hampered in states of renal injury-induced inflammation previously shown to correlate with the transition to myofibroblast-transformed renal Epo-producing cells (MF-REPs). Furthermore, activation of hypoxia-inducible factors (HIFs) by genetic inactivation of HIF-prolyl hydroxylases (PHD1, PHD2, and PHD3) selectively in Epo-producing cells reactivated Epo production in MF-REPs. Loss of PHD2 in REPs restored Epo-gene expression in injured kidneys but caused polycythemia. Notably, combined deletions of PHD1 and PHD3 prevented loss of Epo expression without provoking polycythemia. Mice with PHD-deficient REPs also showed resistance to LPS-induced Epo repression in kidneys, suggesting that augmented HIF signaling counterbalances inflammatory stimuli in regulation of Epo production. Thus, augmentation of HIF signaling may be an attractive therapeutic strategy for treating renal anemia by reactivating Epo synthesis in MF-REPs.

Full Text

Duke Authors

Cited Authors

  • Souma, T; Nezu, M; Nakano, D; Yamazaki, S; Hirano, I; Sekine, H; Dan, T; Takeda, K; Fong, G-H; Nishiyama, A; Ito, S; Miyata, T; Yamamoto, M; Suzuki, N

Published Date

  • February 2016

Published In

Volume / Issue

  • 27 / 2

Start / End Page

  • 428 - 438

PubMed ID

  • 26054543

Pubmed Central ID

  • 26054543

Electronic International Standard Serial Number (EISSN)

  • 1533-3450

Digital Object Identifier (DOI)

  • 10.1681/ASN.2014121184


  • eng

Conference Location

  • United States