epoetin-alfa and Ureteral-Obstruction

The purpose of the work was to investigate mechanisms of erythropoietin-induced protection and accelerated recovery of kidneys and ureters from obstructive injury. Unilateral ureteral obstruction was established for 24, 48, and 72 h in C57BL/6 mice using a non-traumatic micro-clip followed by the microscopic quantification of ureteral peristalsis pre- and post-obstruction. Expression of erythropoietin, erythropoietin receptor, β-common receptor, and downstream apoptosis-related markers was assessed by RT-PCR and immunohistochemistry in ureters and kidneys and compared to the respective organs on the contralateral side within each animal. Expression of genes in kidneys and ureters from mice treated with 20 IU of erythropoietin daily for 72 h prior to obstruction was compared to that of untreated mice following obstruction. Apoptosis in ureteral tissues after 72-h obstruction was assessed via TUNEL assay. Ureteral obstruction increased apoptosis in affected ureters, with peristaltic function halted following all periods of obstruction. Erythropoietin treatment suppressed apoptosis in obstructed tissues and increased the percentage of mice retaining ureteral function immediately following obstruction reversal. Erythropoietin, erythropoietin receptor, Bcl-2, and Bcl-xl mRNA expression were down-regulated, while phospho-Nf-ĸb p65 was up-regulated in ureteral epithelia following obstruction. Erythropoietin treatment induced anti-apoptotic signaling via down-regulated Bax mRNA expression and abrogated phospho-Nf-ĸb p65. Erythropoietin-induced protection of ureteral function and accelerated recovery post-obstruction removal is mediated via anti-apoptotic mechanisms. Ureteral function is disrupted even following obstruction removal, negatively affecting renal function due to delayed recovery. Thus, our results represent a potential target for the development of safe therapeutic agents aimed at improving functional recovery from obstructive injury.

Topics: Animals; Apoptosis; Epoetin Alfa; Female; Kidney; Mice; Mice, Inbred C57BL; Protective Agents; Recovery of Function; Ureter; Ureteral Obstruction

Prevention of fibrosis is a very important therapeutic strategy in the treatment of obstructive nephropathy (ON). The aim of this study is to show and compare the actions of Simvastatin (Simv) and Erythropoietin (Epo) in renal expression of nuclear factor kappa B (NFκB), transforming growth factor-β (TGF-β), basic fibroblast growth factor (bFGF), platelet-derived growth factor B (PDGF-B), fibronectin and development of interstitial fibrosis in rats with unilateral ureteral obstruction (UUO). A total of 48 Sprague-Dawley rats were allocated to 4 groups of sham, Epo, Simv and control. Unilateral ureteral ligation was performed on all rats except the Sham group. For interstitial fibrosis Masson's trichrome stain and for the expression of TGF-β, PDGF-B, bFGF, NFκB and fibronectin, immunohistochemical methods were used. In the Epo and Simv groups, expression of TGF-β and fibronectin and staining with Masson's trichrome were less compared to the control group. In addition, fibronectin expression in the Epo group was less than the Simv group. Unlike the Simv group, NFκB and bFGF expression in the Epo group were less when compared to the control group. Consequently, it was seen that both Epo and Simv prevented fibrosis in ON. Epo was superior in this effect by suppressing the expressions of NFκB and bFGF more effectively than Simv. Based on this finding, Epo might be a better agent than Simv in the prevention of fibrosis in ON.

Topics: Animals; Epoetin Alfa; Erythropoietin; Fibroblast Growth Factor 2; Fibronectins; Fibrosis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunohistochemistry; Kidney; Male; NF-kappa B; Proto-Oncogene Proteins c-sis; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Simvastatin; Transforming Growth Factor beta; Ureteral Obstruction

Topics: Citrulline; Epoetin Alfa; Erythropoietin; Kidney; Kidney Tubules; Recombinant Proteins; Terminology as Topic; Ureteral Obstruction

Erythropoietin (EPO), a member of the cytokine type I superfamily, acts to increase circulating erythrocytes primarily by preventing apoptosis of erythroid progenitors, is known to protect tissues and can raise haemoglobin (Hb) concentrations. Recently, a second receptor for EPO comprising the EPO receptor and beta-common receptor has been reported to mediate EPO-induced tissue protection. EPO modified by carbamylation (CEPO) only signals through this second receptor. Accordingly, we hypothesized that treatment with CEPO, which would not increase Hb concentrations, would protect against tubular damage and thereby inhibit tubulointerstitial injuries.. We evaluated therapeutic effects of CEPO using a rat unilateral ureteral obstruction model.. CEPO decreased tubular apoptosis and alpha-smooth muscle actin (alphaSMA) expression in the absence of polycythaemia, while the untreated obstructed kidneys exhibited increased tubular apoptosis with expanded (alphaSMA) expression. While EPO treatment similarly inhibited tubular apoptosis and alphaSMA expression, EPO treatment increased Hb concentrations and induced a wedge-shaped infarction.. We established a therapeutic approach using CEPO to protect against tubulointerstitial injury. The therapeutic value of this approach warrants further attention and preclinical studies.

Topics: Actins; Animals; Apoptosis; Disease Models, Animal; Epoetin Alfa; Erythropoiesis; Erythropoietin; Hemoglobins; Infarction; Kidney; Kidney Tubules; Male; Rats; Rats, Sprague-Dawley; Receptors, Erythropoietin; Recombinant Proteins; Signal Transduction; Ureteral Obstruction

Topics: Animals; Blood Chemical Analysis; Epoetin Alfa; Erythropoietin; Haplorhini; Hematologic Tests; Humans; Hydronephrosis; Macaca mulatta; Nephrectomy; Pathology; Polycythemia; Replantation; Research; Ureter; Ureteral Obstruction