Erythropoietin and its non-erythropoietic derivative: do they ameliorate renal tubulointerstitial injury in ureteral obstruction?

Abstract

Objectives: Pleiotropic effects of recombinant human erythropoietin (EPO) have recently been discovered in many non-renal animal models. The renoprotective effects of EPO and carbamylated-erythropoietin (CEPO), a novel EPO which has a small stimulatory effect on hemoglobin, have never been explored in unilateral ureteral obstruction (UUO), a chronic tubulointerstitial (TI) disease model which is independent of systemic factors.

Methods: In order to examine the effects of EPO and CEPO treatments on renal TI injury, 36 male Sprague-Dawley rats, weighing 250-320 g, underwent: UUO without treatment (group 1, n = 12), UUO with EPO (groups 2, n = 12), and UUO with CEPO (group 3, n = 12). EPO and CEPO were injected subcutaneously at a dose of 5000 u/kg to each respective rat at 1 day pre-UUO and at day 3, 7 and 10 post-UUO. After days 3, 7, and 14 of UUO, TI injury, collagen, alpha-smooth muscle actin (alpha-SMA) positive cell, ED1-positive cell, terminal deoxynucleotidyl transferase (TdT) mediated nick-end labeling (TUNEL)-positive cell, and transforming growth factor-beta1 (TGF-beta1) messenger ribonucleic acid (mRNA) were determined. Bcl-2 expression was also assessed to verify the mechanism of apoptosis.

Results: At day 14 UUO caused severe TI injury with a significant increase in collagen, alpha-SMA, ED1-positive cell, TUNEL-positive cell, and TGF-beta1 mRNA expression. Administration of EPO and CEPO significantly attenuated TI injury, collagen, ED1-positive cells, and TUNEL-positive cells. Only CEPO-treated rats had decreased alpha-SMA positive cells and TGF-beta1 mRNA. The expression of Bcl-2 was demonstrated only in EPO-treated rats. The hematocrit levels in EPO-treated rats were higher than the control and CEPO-treated rats.

Conclusions: EPO and CEPO can limit 14-day UUO-induced TI injury by reducing inflammation, interstitial fibrosis, and tubular apoptosis.