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Plasticity of renal erythropoietin-producing cells governs fibrosis.

Publication ,  Journal Article
Souma, T; Yamazaki, S; Moriguchi, T; Suzuki, N; Hirano, I; Pan, X; Minegishi, N; Abe, M; Kiyomoto, H; Ito, S; Yamamoto, M
Published in: J Am Soc Nephrol
October 2013

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 NFκB 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 tracing method that marked current and/or previous Epo-producing cells and revealed that the majority of myofibroblasts are derived from REPs. Genetic induction of NFκB activity selectively in REPs resulted in myofibroblastic transformation, indicating that NFκB 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.

Duke Scholars

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Published In

J Am Soc Nephrol

DOI

EISSN

1533-3450

Publication Date

October 2013

Volume

24

Issue

10

Start / End Page

1599 / 1616

Location

United States

Related Subject Headings

  • Urology & Nephrology
  • Ureteral Obstruction
  • Renal Insufficiency, Chronic
  • Phenotype
  • Nephrosclerosis
  • NF-kappa B
  • Myofibroblasts
  • Mice, Knockout
  • Mice
  • Kidney
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Souma, T., Yamazaki, S., Moriguchi, T., Suzuki, N., Hirano, I., Pan, X., … Yamamoto, M. (2013). Plasticity of renal erythropoietin-producing cells governs fibrosis. J Am Soc Nephrol, 24(10), 1599–1616. https://doi.org/10.1681/ASN.2013010030
Souma, Tomokazu, Shun Yamazaki, Takashi Moriguchi, Norio Suzuki, Ikuo Hirano, Xiaoqing Pan, Naoko Minegishi, et al. “Plasticity of renal erythropoietin-producing cells governs fibrosis.J Am Soc Nephrol 24, no. 10 (October 2013): 1599–1616. https://doi.org/10.1681/ASN.2013010030.
Souma T, Yamazaki S, Moriguchi T, Suzuki N, Hirano I, Pan X, et al. Plasticity of renal erythropoietin-producing cells governs fibrosis. J Am Soc Nephrol. 2013 Oct;24(10):1599–616.
Souma, Tomokazu, et al. “Plasticity of renal erythropoietin-producing cells governs fibrosis.J Am Soc Nephrol, vol. 24, no. 10, Oct. 2013, pp. 1599–616. Pubmed, doi:10.1681/ASN.2013010030.
Souma T, Yamazaki S, Moriguchi T, Suzuki N, Hirano I, Pan X, Minegishi N, Abe M, Kiyomoto H, Ito S, Yamamoto M. Plasticity of renal erythropoietin-producing cells governs fibrosis. J Am Soc Nephrol. 2013 Oct;24(10):1599–1616.

Published In

J Am Soc Nephrol

DOI

EISSN

1533-3450

Publication Date

October 2013

Volume

24

Issue

10

Start / End Page

1599 / 1616

Location

United States

Related Subject Headings

  • Urology & Nephrology
  • Ureteral Obstruction
  • Renal Insufficiency, Chronic
  • Phenotype
  • Nephrosclerosis
  • NF-kappa B
  • Myofibroblasts
  • Mice, Knockout
  • Mice
  • Kidney