Plasticity of renal erythropoietin-producing cells governs fibrosis

Tomokazu Souma, Shun Yamazaki, Takashi Moriguchi, Norio Suzuki, Ikuo Hirano, Xiaoqing Pan, Naoko Minegishi, Michiaki Abe, Hideyasu Kiyomoto, Sadayoshi Ito, Masayuki Yamamoto

Research output: Contribution to journalArticlepeer-review

102 Citations (Scopus)

Abstract

CKD progresses with fibrosis and erythropoietin (Epo)-dependent anemia, leading to increased cardiovascular complications, but the mechanisms linking Epo-dependent anemia and fibrosis remain unclear. Here, we show that the cellular phenotype of renal Epo-producing cells (REPs) alternates between a physiologic Epo-producing state and a pathologic fibrogenic state in response to microenvironmental signals. In a novel mouse model, unilateral ureteral obstruction-induced inflammatory milieu activated NFkB and Smad signaling pathways in REPs, rapidly repressed the Epo-producing potential of REPs, and led to myofibroblast transformation of these cells. Moreover, we developed a unique Cre-based cell-fate tracingmethod thatmarked current and/or previous Epo-producing cells and revealed that themajority of myofibroblasts are derived from REPs. Genetic induction of NFkB activity selectively in REPs resulted in myofibroblastic transformation, indicating that NFkB signaling elicits a phenotypic switch. Reversing the unilateral ureteral obstruction-induced inflammatory microenvironment restored the Epo-producing potential and the physiologic phenotype of REPs. This phenotypic reversion was accelerated by anti-inflammatory therapy. These findings demonstrate that REPs possess cellular plasticity, and suggest that the phenotypic transition of REPs to myofibroblasts, modulated by inflammatory molecules, underlies the connection between anemia and renal fibrosis in CKD.

Original languageEnglish
Pages (from-to)1599-1616
Number of pages18
JournalJournal of the American Society of Nephrology
Volume24
Issue number10
DOIs
Publication statusPublished - 2013 Oct

ASJC Scopus subject areas

  • Nephrology

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