Renal erythropoietin-producing cells in health and disease.

Masayuki Yamamoto,Norio Suzuki,Tomokazu Souma

doi:10.3389/fphys.2015.00167

Masayuki Yamamoto, Norio Suzuki + Show 1 more

Open Access

https://doi.org/10.3389/fphys.2015.00167

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Abstract

Erythropoietin (Epo) is an indispensable erythropoietic hormone primarily produced from renal Epo-producing cells (REPs). Epo production in REPs is tightly regulated in a hypoxia-inducible manner to maintain tissue oxygen homeostasis. Insufficient Epo production by REPs causes renal anemia and anemia associated with chronic disorders. Recent studies have broadened our understanding of REPs from prototypic hypoxia-responsive cells to dynamic fibrogenic cells. In chronic kidney disease, REPs are the major source of scar-forming myofibroblasts and actively produce fibrogenic molecules, including inflammatory cytokines. Notably, myofibroblast-transformed REPs (MF-REPs) recover their original physiological properties after resolution of the disease insults, suggesting that renal anemia and fibrosis could be reversible to some extent. Therefore, understanding the plasticity of REPs will lead to the development of novel targeted therapeutics for both renal fibrosis and anemia. This review summarizes the regulatory mechanisms how hypoxia-inducible Epo gene expression is attained in health and disease conditions.

Highlights

Erythropoietin (Epo) is an indispensable erythropoietic glycoprotein hormone that induces red blood cell production (Haase, 2010; Bunn, 2013; Suzuki, 2015)
By using a transgenic mouse technology, SV40 T antigen cDNA was integrated into the Epo gene locus to identify renal Epo-producing cells (REPs) with anti-T antigen antibodies (Maxwell et al, 1993), and the results showed that renal fibroblasts are the top candidates among the proposed Epo-producing cells including tubular epithelial cells, glomerular mesangial cells, and interstitial fibroblasts
A few renal interstitial cells are labeled by both strategies under normal conditions, whereas green fluorescent protein (GFP)-positive cells robustly emerge and increase in the kidneys under anemic or hypoxic stress. These GFP-positive cells in the interstitium are fibroblast-like cells expressing neural genes [e.g., microtubule-associated protein 2 (Map2), nerve growth factor receptor (Ngfr), and neurofilament light peptide (Nefl)]

Summary

Introduction

Erythropoietin (Epo) is an indispensable erythropoietic glycoprotein hormone that induces red blood cell production (Haase, 2010; Bunn, 2013; Suzuki, 2015). A few renal interstitial cells are labeled by both strategies under normal conditions, whereas GFP-positive cells robustly emerge and increase in the kidneys under anemic or hypoxic stress These GFP-positive cells in the interstitium are fibroblast-like cells expressing neural genes [e.g., microtubule-associated protein 2 (Map2), nerve growth factor receptor (Ngfr), and neurofilament light peptide (Nefl)]. We named these cells renal erythropoietin-producing cells, or REPs (Suzuki et al, 2007; Obara et al, 2008)

Epo Gene Modification for Further Analyses of REPs

Regulatory Mechanisms Governing Epo Synthesis

REPs as Major Contributors to Renal Fibrosis

Endothelial cell

Plasticity of REPs

Environmental Cues for Myofibroblast Transformation

Findings

Effect of Hypoxia on Epo Production and Kidney Diseases