Epoetin Delta Reduces Oxidative Stress in Primary Human Renal Tubular Cells

Abstract

Erythropoietin (EPO) exerts (renal) tissue protective effects. Since it is unclear whether this is a direct effect of EPO on the kidney or not, we investigated whether EPO is able to protect human renal tubular epithelial cells (hTECs) from oxidative stress and if so which pathways are involved. EPO (epoetin delta) could protect hTECs against oxidative stress by a dose-dependent inhibition of reactive oxygen species formation. This protective effect is possibly related to the membranous expression of the EPO receptor (EPOR) since our data point to the membranous EPOR expression as a prerequisite for this protective effect. Oxidative stress reduction went along with the upregulation of renoprotective genes. Whilst three of these, heme oxygenase-1 (HO-1), aquaporin-1 (AQP-1), and B-cell CLL/lymphoma 2 (Bcl-2) have already been associated with EPO-induced renoprotection, this study for the first time suggests carboxypeptidase M (CPM), dipeptidyl peptidase IV (DPPIV), and cytoglobin (Cygb) to play a role in this process.

Mechanisms of Neuroprotection from Hypoxia-Ischemia (HI) Brain Injury by Up-regulation of Cytoglobin (CYGB) in a Neonatal Rat Model

“…Due to its NO dioxygenase activity (56 -58), CYGB might reduce intracellular NO concentration, which in turn may prevent accumulation of peroxynitrite, a strong oxidant formed from the reaction between superoxide and NO. It has been speculated that CYGB, like other hexacoordinated globins, may eliminate reactive oxygen species utilizing heme and thiol residues (59,60), and it has been found that CYGB may reduce the induction of intracellular reactive oxygen species formation (55,61). The processes of lipid-induced transformation of CYGB from hexacoordinate to pentacoordinate may allow the cell to up-regulate antioxidant defenses before extensive oxidative damage occurs (62).…”

Reactive Oxygen Species in Health and Disease

“…The protective antioxidant capability of epoetin   δ   was then assessed using a commercial oxidative status indicator (2′, 7′-dichlorodihydrofluorescein diacetate; H 2 DCFDA). The authors have demonstrated that epoetin   δ   antioxidant capacity has protected the renal tissue through upregulation of several renoprotective genes, some of them, as carboxypeptidase M, dipeptide peptidase IV, and cytoglobin, were reported for the first time to be involved in the antioxidant renoprotection process [105]. …”

Cytoglobin: biochemical, functional and clinical perspective of the newest member of the globin family

“…Recent studies have demonstrated that NFAT and AP1 induce Cygb expression, thus mediating calcineurin signalling [55]. Moreover, Cygb expression has been found as a downstream target of tumour growth factor b (TGF-b), platelet-derived growth factor, protein kinase C [26] and EPO signalling [56]. The Cygb signalling pathway is illustrated in Fig.…”