Epoetin Delta as an Antifibrotic Agent in the Remnant Kidney Rat: A Possible Role for Transforming Growth Factor Beta and Hepatocyte Growth Factor

Abstract

Background/Aims:Erythropoiesis-stimulating agents (ESAs) may have therapeutic benefits beyond ameliorating anemia. Although ESAs have renoprotective effects in acute/chronic renal injury models, their effects on blood pressure could also worsen chronic renal failure (CRF). The development of human cell-derived erythropoietin analogue epoetin delta prompted us (1) to investigate whether in a 5/6th nephrectomy-induced CRF rat model, epoetin delta-mediated renoprotective effects occur independently of its hematopoietic effects and (2) to unravel the involvement of particular factors herein. Methods: After induction of CRF in Wistar rats, epoetin delta was administered for 8 weeks at different doses: 0 IU/kg (uremic control); 48, 100 or 300 IU/kg 1×/week, and 16 or 100 IU/kg 3×/week. During this period hematopoietic and renal functional parameters as well as systolic blood pressure (SBP) were monitored. Results: After 8 weeks, control CRF rats showed reduced hematocrit (Hct)/hemoglobin (Hb) levels and increased SBP. Epoetin delta dose-dependently attenuated the reduction in Hct/Hb. Furthermore, epoetin delta treatment resulted in reduced deterioration of renal function in CRF rats after 8 weeks which was accompanied by decreased collagen deposition, renal fibrosis and interstitial macrophage infiltration. Remarkably, these renoprotective effects did not show the same dose dependency as compared to that seen for the hematopoietic response and were also seen at subhematopoietic doses. Interestingly, epoetin delta treatment resulted in a dose-dependent decrease of profibrotic (TGF-β) and proapoptotic (Bcl-2-associated X protein) genes together with a significant dose-dependent increase of antifibrotic (hepatocyte growth factor) and antiapoptotic (Bcl-2) genes. Epoetin delta treatment had no effect on VEGF expression. Conclusion: Epoetin delta treatment could delay the progression of CRF through antiapoptotic and antifibrotic mechanisms. This protective action of epoetin delta on the kidney probably is not directly related to its hematopoietic effects.

Erythropoietin ameliorates genetamicin-induced renal toxicity: A biochemical and histopathological study

“…In another study conducted by Rjiba-Touati et al to find the protective effect of erythropoietin against Cisplatin-induced apoptosis in rat kidney, a reduction of apoptosis by up regulation of antiapoptotic protein expressions, down regulation of pro apoptotic protein levels, and reduction of caspase-3 activity in male Wistar rats was seen (40). Hence it seems that the protective action of Eprex on the kidney probably is not directly related to its hematopoietic effects (14). Furthermore, various beneficial effects of erythropoietin in preventing aristolochic acid-induced apoptosis in the cultured cells were investigated by Wang et al (41).…”

“…Erythropoietin is a cytokine that is produced primarily in the kidneys by renal cortical fibroblasts (10,11), and which regulates the differentiation and proliferation of erythroid progenitor cells. However, due to in-vitro human recombinant erythropoietin stimulates endothelial cell proliferation (10)(11)(12) and angiogenesis (10,13,14), erythropoietin effects may not be limited to bone marrow cells. Moreover, it has been shown to exert pleiotropic properties, such as cytoprotection, anti-inflammation and antiapoptosis, in the central nervous, kidney and liver (12)(13)(14)(15).…”

“…However, due to in-vitro human recombinant erythropoietin stimulates endothelial cell proliferation (10)(11)(12) and angiogenesis (10,13,14), erythropoietin effects may not be limited to bone marrow cells. Moreover, it has been shown to exert pleiotropic properties, such as cytoprotection, anti-inflammation and antiapoptosis, in the central nervous, kidney and liver (12)(13)(14)(15). Studies also suggested that erythropoietin may act directly on damaged tubular cells and stimulates their regeneration (9,15).…”

“…It has been shown that erythropoietin receptors are found on renal tubular epithelial, mesangial and endothelial cells. This effect may be through activation signaling pathways to prevent apoptosis and/ or stimulate reparative proliferation of the injured cells (9,14,15). Gentamicin (GM) is widely known to induce ARF as a result of renal tubular epithelial cell injury by direct acute tubular necrosis which is primarily localized to the proximal tubule.…”

Small Vessels, Big Role

“…Hepatocyte growth factor (HGF) is a pleiotropic cytokine with distinct renoprotective roles, as has been demonstrated in diabetes-induced renal injury, acute, and chronic renal ischemia 10, 79, 80 . HGF promotes tissue healing by stimulating mobilization of cell progenitors, by interactions with VEGF 81 to promote MV proliferation and repair, and by counteracting renal inflammation, fibrosis, and apoptosis via TGF-β, NFkB, and Bax/BcL inhibition 10, 80, 82-84 . Reduced bioavailability of this factor significantly accelerates development of MV rarefaction, renal inflammation and fibrosis 10, 80, 83 supporting an important role of HGF to protect the renal parenchyma and preserve the renal microvasculature.…”