Anticancer therapy may be chased with kidney damage exemplified by disturbed tubular and/or glomerular function (Denker et al., 2011; Lameire et al., 2010). The most common unfavorable kidney effects of childhood cancer chemotherapy include acute renal injury, tubulointerstitial disorder, capillary endothelial damage and electrolytes as well as acid-base disturbances (Salahudeen et al., 2013). Renal disorders occurring with chemotherapeutic drugs are caused by low renal blood supply, tubular obstruction, renal parenchymal and microvascular structural damage (Lameire et al., 2011; Salahudeen et al., 2013; Perazella et al., 2012).
One of the broadly used anticancer drugs is methotrexate (MTX) that acts as typical antifolate (Allegra, 1990). Unlike other oncotherapeutics, MTX is characterized by safety administration with a wide range of dosage in treatment of many diseases such as rheumatoid arthritis, psoriasis and acute lymphoblastic leukemia (Albertioni et al., 1995; Bright, 1999) and can be combined with leucovorin rescue in doses ranged between 1,000–33,000 mg/m2 (Balis et al., 1985). This large dose of MTX is called high-dose methotrexate (HDMTX) which is given by delayed i.v. infusion in the patients with the normal function of the kidney following their excess fluid intake and alkalinization to obtain the drug solubility in urine. Co-administration of leucovorin greatly protects against fatal MTX toxicity (Brigitte and Peter, 2006). However, MTX-induced nephrotoxicity endures even though infrequently with these protective measures. Since MTX is removed through excretion from the kidney, however, MTX-induced renal disturbed function is associated with an interrupted MTX removal resulting in continuous elevation of plasma concentration of MTX that may produce unsuccessful protection by leucovorin with a subsequent obvious development of MTX-toxic manifestations predominantly myelosuppression as well as hepatic, cutaneous and mucosal inflammation (Stark et al., 1989). MTX-induced disturbed renal function is attributed to MTX and its metabolites’ precipitation within the renal tubules (Messmann and Allegra, 2001). In addition, the risk of renal dysfunction is augmented with the short-timed i.v. infusion of HDMTX which results in a greater concentration of MTX in both plasma and urine. Moreover, a lot of drugs such as nonsteroidal anti-inflammatory, penicillin, probenecid, and sulfisoxazole when concomitantly given with MTX, they have been accompanied by enhanced nephrotoxicity due to their interference with excretion of MTX from the kidney and by challenging in the renal tubular secretion (Brigitte and Peter, 2006). Development of MTX- induced renal dysfunction is indicated by sudden elevation of serum creatinine together with a significant increase of the concentration of MTX in the plasma (Lawrenz-Wolf et al., 1994; Widemann et al., 1997). Furthermore, a significant hepatic dysfunction associating HDMTX therapy has not essentially been accompanied by renal failure development (Brigitte and Peter, 2006).
Erythropoietin (EPO) considered as a growth factor, is crucial in cell proliferation and neovascularization. In addition, EPO biochemically is a glycoprotein released by interstitial cells, found in a soluble form in the circulation, and promotes erythropoiesis. Recombinant human erythropoietin, as well, largely treats anemic patients with the end-stage kidney disorder and patients with allograft kidney (Moore and Bellomo, 2011; Yasari et al., 2012 and Nemati and Abbaszadeh, 2012). Moreover, it is applied to guard renal tissue against reperfusion damage (Vesey et al., 2004). EPO is recently evidenced to have several additional biological tasks that can keep the brain (Yu et al., 2016), the heart (Rong and Xijun, 2015), the liver (Bejaoui et al., 2015; Liu et al., 2015) and the kidney (Zou et al., 2016) in case of ischemic renal injury (IRI) despite the actual molecular pathogenesis of EPO self-protective effect remains indistinct. However, toll-like receptors (TLRs) are thought to be the keystone molecules in the regulation of inflammatory responses. Also, significantly increased expression of TLR4 from the renal tubular epithelial cells is confirmed and therefore, it activates the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and helps the expression of various inflammatory factors detected in IRI (Jing-Guang et al., 2016).
One of the essential side effects of oncotherapeutic drugs is nephrotoxicity that is distinguished by a diminished glomerular filtration rate and renal blood supply (Launay-Vacher et al., 2008; Ravindra et al., 2010). The ameliorating and defensive effect of recombinant human erythropoietin against cisplatin-induced nephrotoxicity was stated in female (Yalcin et al., 2003) and male (Lee et al., 2009) rats as well as in other experimental animals (Lee et al., 2009; Rjiba-Touati et al., 2011; Rjiba-Touati et al., 2012; Mohamed et al., 2013).
The main objective of this study was to show the erythropoietin’s role in the methotrexate-induced nephrotoxicity in male rats and to determine its protective and improving effects against methotrexate provoked renal injury.