Erythropoietin ameliorates renal interstitial fibrosis via the inhibition of fibrocyte accumulation

Abstract

Abstract. Erythropoietin (EPO) is a hematopoietic hormone that protects against renal interstitial fibrosis in animal models; however, the mechanism underlying the anti-fibrotic activity of EPO has remained elusive. The present study aimed to elucidate this mechanism. Twenty-four male C57BL6 mice were randomly divided into four groups, each comprising six mice: i) control group (Sh); ii) unilateral ureteral obstruction (UUO) plus vehicle group (U+V); ⅲ) UUO plus 300 U/kg body weight recombinant human (rh)EPO (U+E1) and ⅳ) UUO plus 1,000 U/kg body weight rhEPO (U+E2). Seven days post-surgery, the mice were sacrificed for examination. UUO induced significant deposition of extracellular matrix, detected by picro-sirius red staining, which was decreased following rhEPO treatment. UUO also induced deposition of collagen I and fibronectin, rhEPO treatment was able to attenuate this effect at protein and mRNA levels. Compared with the control groups, UUO resulted in the accumulation of α-smooth muscle actin-positive cells in the interstitium, an effect which was ameliorated by rhEPO. Furthermore, rhEPO abrogated the UUO-induced increase in the number of bone marrow-derived myofibroblasts. Mechanistically, it was discovered that rhEPO decreased CXC chemokine ligand 16 (CXCL16) expression at protein level. However, treatment with rhEPO did not alter the protein expression of CC chemokine ligand 21 or CXCL12. These results suggested that rhEPO decreased fibrocyte accumulation via the suppression of renal CXCL16, which resulted in the attenuation of renal fibrosis. IntroductionChronic kidney disease induces irreversible kidney damage, and progressive renal fibrosis is frequently observed regardless of the underlying cause of the disease (1). The major effector cells that are associated with the development of progressive renal fibrosis are the interstitial myofibroblasts (2). Interstitial myofibroblasts have been proposed to originate from five potential sources, including circulating fibrocytes, pericytes, fibroblasts, the tubular epithelial-mesenchymal transition (EMT) and the endothelial-mesenchymal transition (3).Fibrocytes are bone marrow-derived mesenchymal progenitor cells, which express hematopoietic stem cell antigens, monocytic lineage markers and fibroblast products (4). Fibrocytes constitutively produce extracellular matrix (ECM) components, in addition to ECM-modifying enzymes, and are able to differentiate into myofibroblasts in vitro and in vivo under certain micro-environmental conditions (5). There is an increasing body of evidence suggesting that these cells contribute to the development of the novel myofibroblast population that is responsible for the production of ECM during renal fibrosis (6-11).Erythropoietin (EPO) is a hematopoietic hormone, the majority of which is produced by the adult kidneys. In addition to its erythropoietic effects, EPO exerts protective effects against acute ischemic and toxic renal injuries (12)(13)(14). EPO also protects against interstitial injuries, including interstitial ...

Role of Circulating Fibrocytes in Cardiac Fibrosis

“…[ 58 ] In response to injuries such as inflammation and hypoxia, the concentrations of chemokines in both peripheral blood and organs are elevated, and this elevation leads to accumulation of circulating fibrocytes in blood stream and injured organs. [ 59 60 ] This has been shown in many studies. For example, CXC-chemokine ligand 16 (CXCL16) (a transmembrane CXC chemokine) knockout mice administrated with angiotensin II (Ang II) were found to have significantly less circulating fibrocytes in injured kidney compared with these in wild-type mice,[ 61 ] indicating CXCL16 is one of the mediators involved in circulating fibrocyte recruitment.…”

Pleiotropic and Renoprotective Effects of Erythropoietin Beta on Experimental Diabetic Nephropathy Model

“…A search of the literature shows that recombinant human erythropoietin and its synthetic derivatives (at least epoetin beta and methoxy polyethylene glycol-epoetin beta) have anti-oxidant, anti-inflammatory and cytoprotective properties [17,18,19,22,23,24,25]. But it cannot be concluded that different synthetic derivatives of epoetin may offer the same effects on cytoprotection, possibly a result that may reflect different affinities binding to the EPOR.…”

“…Lu et al [24] reported that epoetin beta inhibits cardiac fibrosis in the experimental diabetes model. Recently, Geng et al [25] reported that epoetin ameliorates renal interstitial fibrosis in the experimental unilateral ureteral obstruction model. Furthermore, epoetin abrogated the unilateral ureteral obstruction induced increase in the number of bone marrow-derived myofibroblasts.…”

Advances in Understanding the Effects of Erythropoietin on Renal Fibrosis

“…However, under pathologic conditions the resident renal fibroblasts transdifferentiate into myofibroblasts, which promote renal fibrosis by producing large amounts of extracellular matrix proteins rather than EPO (52). A study of mice showed that treatment with rhEPO significantly inhibited the accumulation of fibrocyte by inhibition of α-SMA upregulation, and thereby attenuating renal interstitial fibrosis (53). Another study of transgenic mice found that enhanced signaling mediated by hypoxia-inducible factor (HIF) in myofibroblast-transformed renal EPO-producing cells reactivated the synthesis of EPO, without influencing renal fibrosis or inflammation (54).…”