Erythropoietin protects podocytes from damage by advanced glycation end-products.
BACKGROUND
Podocyte damage and accumulation of advanced glycation end-products (AGEs) are implicated in the development and progression of diabetic nephropathy. We have previously shown that changes in podocyte pathophysiology, such as hypertrophy and reduced migration, are closely linked with the induction of the cell cycle inhibitor p27(Kip1) and a decrease in neuropilin-1 (NRP1) expression. We investigated whether the erythropoietin receptor activators CERA and epoetin-β may prevent AGE-mediated changes in podocytes.


METHODS
Differentiated mouse podocytes in culture were challenged by AGE-modified bovine serum albumin (BSA) or control BSA in the presence or absence of CERA as well as epoetin-β. Cell cycle analysis and determination of apoptosis markers were performed. p27(Kip1) and NRP1 expression was measured by RT-PCR and Western blots.


RESULTS
Differentiated mouse podocytes in culture expressed erythropoietin receptors which were phosphorylated after incubation with CERA or epoetin-β. CERA or epoetin-β prevented the p27(Kip1)-dependent cell cycle arrest and cellular hypertrophy induced by AGE-BSA incubation. Furthermore, the p27(Kip1)-dependent AGE-BSA-induced decrease in cell viability and decrease in cell proliferation was ameliorated in the presence of CERA or epoetin-β. Following erythropoietin treatment, AGE-BSA failed to further reduce NRP1 expression, resulting in improved podocyte migration.


CONCLUSIONS
Treatment with the erythropoietin receptor activators epoetin-β or CERA protected podocytes from AGE-BSA-mediated damage via an effect on p27(Kip1) and NRP1 expression. Consequently, early treatment with erythropoietin may help to prevent diabetic nephropathy.
Ruester
Christiane
C
Department of Internal Medicine III, Friedrich Schiller University, Jena, Germany.
Franke
Sybille
S
Bondeva
Tzvetanka
T
Wolf
Gunter
G
D000818:Animals; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004921:Erythropoietin / Q000494:pharmacology*; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D051379:Mice; D039942:Neuropilin-1 / Q000235:genetics; D050199:Podocytes / Q000187:drug effects*; D011092:Polyethylene Glycols / Q000494:pharmacology; D017467:Receptors, Erythropoietin / Q000096:biosynthesis / Q000187:drug effects; D011994:Recombinant Proteins; D012710:Serum Albumin, Bovine / Q000494:pharmacology*
D017127:Glycation End Products, Advanced; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; C081628:advanced glycation end products-bovine serum albumin; C508420:continuous erythropoietin receptor activator; C103998:epoetin beta; D004921:Erythropoietin; D039942:Neuropilin-1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D012710:Serum Albumin, Bovine; D011092:Polyethylene Glycols