Plasticity of Renal Erythropoietin-Producing Cells Governs Fibrosis

• Published in: Journal of the American Society of Nephrology Vol. 24; no. 10; pp. 1599 - 1616
• Main Authors: SOUMA, Tomokazu, YAMAZAKI, Shun, YAMAMOTO, Masayuki, MORIGUCHI, Takashi, SUZUKI, Norio, HIRANO, Ikuo, XIAOQING PAN, MINEGISHI, Naoko, ABE, Michiaki, KIYOMOTO, Hideyasu, ITO, Sadayoshi
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society of Nephrology 01.10.2013
• Subjects: Anemia - etiology; Animals; Basic Research; Biological and medical sciences; DNA Modification Methylases - metabolism; Erythropoietin - biosynthesis; Kidney - metabolism; Kidney - pathology; Kidneys; Medical sciences; Mice; Mice, Knockout; Myofibroblasts - cytology; Myofibroblasts - pathology; Nephrology. Urinary tract diseases; Nephrosclerosis - etiology; Nephrosclerosis - metabolism; Nephrosclerosis - pathology; NF-kappa B - metabolism; Phenotype; Renal Insufficiency, Chronic - complications; Renal Insufficiency, Chronic - metabolism; Renal Insufficiency, Chronic - pathology; Ureteral Obstruction - metabolism; Ureteral Obstruction - pathology; Urinary system involvement in other diseases. Miscellaneous; Kidney disease; Nephrology; Urinary system disease; Erythropoietin; Polypeptide; Renal fibrosis; Plasticity; Urology
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/asn.2013010030

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.