Erythropoietin protects against rhabdomyolysis-induced acute kidney injury by modulating macrophage polarization

Abstract

Erythropoietin (EPO) is a well-known hormone that is clinically used for the treatment of anemia. Very recently, an increasing body of evidence showed that EPO could still regulate bioactivities of macrophages. However, the details about the immunomodulatory effect of EPO on macrophages are not fully delineated, particularly in the setting of renal damages. Therefore, in the present study, we determined whether EPO could exert an impact on the dynamics of macrophages in a well-established model of rhabdomyolysis-induced acute kidney injury and explored the potential mechanisms. EPO was found to ameliorate kidney injuries by reducing macrophages recruitment and promoting phenotype switch toward M2 macrophages in vivo. It was also confirmed that EPO could directly suppress pro-inflammatory responses of M1 macrophages and promote M2 marker expression in vitro. Data indicated the possible involvement of Jak2/STAT3/STAT6 pathway in the augmentation of EPO on M2 polarization. These results improved the understanding of the immunoregulatory capacity of EPO on macrophages, which might optimize the therapeutic modalities of EPO.

Loganetin protects against rhabdomyolysis‐induced acute kidney injury by modulating the toll‐like receptor 4 signalling pathway

“…To investigate the levels of proteins in the TLR4‐related signalling pathway, such as TLR4, phospho‐NF‐κB p65 (p‐p65) or nonphospho‐NF‐κB p65 (p65), JNK, p‐JNK, p38, p‐p38, p21, c‐Jun , , and cleaved caspase‐3, kidney‐paraffin blocks and tissues were subjected to immunohistochemistry, immunofluorescence, and immunoblot analysis. As in previous studies (Wang, Zhang, et al, ; Zhang, Wang, et al, ), the kidney‐paraffin sections were rehydrated through a graded series of ethanol and then incubated in 0.3% H 2 O 2 overnight at 4°C to block endogenous peroxidase activity. Specific primary antibodies were incubated for 12 hr at 4°C in different dilutions (p‐p65, p65, JNK, p38, 1:100; p‐JNK, p‐p38, p21, 1:150; c‐Jun, Bax, cleaved caspase‐3, 1:200).…”

In vitro modifying effect of erythropoietin upon thymic lymphocytes: an inhibitor analysis

“…E.g., antioxidant in vivo eff ects of EPO (reduced lipid peroxidation in blood lymphocytes) are shown by Osikov et al [3]. Immunotropic eff ects of EPO are recently studied, due to its immunomodulatory eff ects under clinical and experimental conditions [4][5][6]. Response of lymphocytes and macrophages to EPO seems to be mediated by the EPO receptors on their surface [7].…”

Potent Therapy and Transcriptional Profile of Combined Erythropoietin Derived Peptide CHBP and Caspase-3 siRNA against Kidney Ischemia/Reperfusion Injury in mice

“…Recently, the innate repair mechanism in AKI has attracted great attention, which is highlighted by an innate repair receptor, a heterodimer of erythropoietin (EPO) receptor and β common receptor (EPOR/βcR) (Brines and Cerami 2012). EPO, a natural ligand of EPOR/βcR, is defective in tissue protection due to low a nity, but high a nity to a homodimer receptor (EPOR) 2 in erythropoiesis (Gobe et al, 2014;Wang et al, 2017;Shi et al, 2018). EPO-derived helix B surface peptide (HBSP) and cyclic HBSP (CHBP, more stable and potent than HBSP (Yang et al, 2014b)) only bind with EPOR/βcR, so remaining the tissue protective property without erythropoiesis, and have promising potential for clinical application (Brines et al, 2008;Patel et al, 2012;Wu et al, 2013;Yang et al, 2013).…”