Epoetin delta as an antifibrotic agent in the remnant kidney rat: a possible role for transforming growth factor beta and hepatocyte growth factor.
OBJECTIVE
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 1x/week, and 16 or 100 IU/kg 3x/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-beta) 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.


CONCLUSIONS
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.
De Beuf
Annelies
A
Laboratory of Pathophysiology, Faculties of Medicine and Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Antwerp, Belgium.
D'Haese
Patrick C
PC
Verhulst
Anja
A
D000740:Anemia / Q000188:drug therapy; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D004921:Erythropoietin / Q000627:therapeutic use*; D005355:Fibrosis; D006397:Hematinics / Q000627:therapeutic use; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000188:drug therapy*; D008297:Male; D009392:Nephrectomy; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000502:physiology*; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis
D006397:Hematinics; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D051028:bcl-2-Associated X Protein; D004921:Erythropoietin; C516023:epoetin delta; D017228:Hepatocyte Growth Factor