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Plasticity of renal erythropoietin-producing cells governs fibrosis.

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 NF?B 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 NF?B activity selectively in REPs resulted in myofibroblastic transformation, indicating that NF?B 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.

SUBMITTER: Souma T

PROVIDER: S-EPMC3785278 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Plasticity of renal erythropoietin-producing cells governs fibrosis.

Souma Tomokazu T Yamazaki Shun S Moriguchi Takashi T Suzuki Norio N Hirano Ikuo I Pan Xiaoqing X Minegishi Naoko N Abe Michiaki M Kiyomoto Hideyasu H Ito Sadayoshi S Yamamoto Masayuki M

Journal of the American Society of Nephrology : JASN 20130705 10

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 activate ...[more]

PMID: 23833259

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Project description:Background Renal erythropoietin (EPO)-producing (REP) cells produce EPO through hypoxia-inducible factor (HIF) 2α-activated gene transcription. Insufficient EPO production leads to anemia in patients with chronic kidney disease. Although recombinant EPO is effective to improve anemia, no reliable REP cell lines limit further progress of research and development of novel treatment. Methods We screened Epo mRNA expression in mouse fibroblast cell lines. Small interfering RNA specific for HIF1α or HIF2α was transfected to study Epo expression in C3H10T1/2 cells. The effect of transforming growth factor-β1 (TGF-β1) on HIF-EPO axis was studied in C3H10T1/2 cells and mice. Results Similar to mouse REP pericytes, C3H10T1/2 cells differentiated to α-smooth muscle actin+ myofibroblasts after exposure to TGF-β1. Specific HIF knockdown demonstrated the role of HIF2α in hypoxia-induced Epo expression. Sustained TGF-β1 exposure increased neither DNA methyltransferase nor methylation of Epas1 and Epo genes. However, TGF-β1 repressed HIF2α-encoding Epas1 promptly through activating activin receptor-like kinase-5 (ALK5), thereby decreasing Epo induction by hypoxia and prolyl hydroxylase domain inhibitor roxadustat. In mice with pro-fibrotic injury induced by ureteral obstruction, upregulation of Tgfb1 was accompanied with downregulation of Epas1 and Epo in injured kidneys and myofibroblasts, which were reversed by ALK5 inhibitor SB431542. Conclusion C3H10T1/2 cells possessed the property of HIF2α-dependent Epo expression in REP pericytes. TGF-β1 induced not only the transition to myofibroblasts but also a repressive effect on Epas1-Epo axis in C3H10T1/2 cells. The repressive effect of TGF-β1 on Epas1-Epo axis was confirmed in REP pericytes in vivo. Inhibition of TGF-β1-ALK5 signaling might provide a novel treatment to rescue EPO expression in REP pericytes of injured kidney. Supplementary Information The online version contains supplementary material available at 10.1186/s12929-021-00770-2.

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Plasticity of renal erythropoietin-producing cells governs fibrosis.

Publications

Plasticity of renal erythropoietin-producing cells governs fibrosis.

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