Effects of erythropoietin receptor activity on angiogenesis, tubular injury, and fibrosis in acute kidney injury: a “U-shaped” relationship

Abstract

The erythropoietin receptor (EpoR) is widely expressed but its renoprotective action is unexplored. To examine the role of EpoR in vivo in the kidney, we induced acute kidney injury (AKI) by ischemia-reperfusion in mice with different EpoR bioactivities in the kidney. EpoR bioactivity was reduced by knockin of wild-type human EpoR, which is hypofunctional relative to murine EpoR, and a renal tubule-specific EpoR knockout. These mice had lower EPO/EpoR activity and lower autophagy flux in renal tubules. Upon AKI induction, they exhibited worse renal function and structural damage, more apoptosis at the acute stage (<7 days), and slower recovery with more tubulointerstitial fibrosis at the subacute stage (14 days). In contrast, mice with hyperactive EpoR signaling from knockin of a constitutively active human EpoR had higher autophagic flux, milder kidney damage, and better renal function at the acute stage but, surprisingly, worse tubulointerstitial fibrosis and renal function at the subacute stage. Either excess or deficient EpoR activity in the kidney was associated with abnormal peritubular capillaries and tubular hypoxia, creating a "U-shaped" relationship. The direct effects of EpoR on tubular cells were confirmed in vitro by a hydrogen peroxide model using primary cultured proximal tubule cells with different EpoR activities. In summary, normal erythropoietin (EPO)/EpoR signaling in renal tubules provides defense against renal tubular injury maintains the autophagy-apoptosis balance and peritubular capillary integrity. High and low EPO/EpoR bioactivities both lead to vascular defect, and high EpoR activity overides the tubular protective effects in AKI recovery.

PPAR γ/TLR4/TGF-β1 axis mediates the protection effect of erythropoietin on cyclosporin A-induced chronic nephropathy in rat

“…Acikgoz' study showed that the antifibrotic effect of EPO on rats with obstructive renal fibrosis may be regulated by nuclear factor kappa B (NF-rB) signaling pathway [17]. Shi et al [18] showed that EPO can protect acute renal ischemiareperfusion injury in mice and is closely related to the activity of EPO receptor. However, the other study suggested that although EPO has protective effects on renal function and structure in renal ischemia-reperfusion injury, the extraphysiological dose required for renal protection contributes to fibrosis and chronic kidney disease [9], which inconsistent with our results.…”

The tripartite interaction of phosphate, autophagy, and αKlotho in health maintenance

“…The fibrotic area and fibrosis intensity were quantified with Image J program with established methods. 40,41,47…”

“…Four-micrometer sections of paraffin-embedded kidney were subjected to immunohistochemistry following established protocols. 36,40,41,47 Total kidney lysate covering all kidney zones were prepared and subjected to SDS-PAGE as described. 40,47…”

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).…”