title: The effect of low-dose Continuous Erythropoietin receptor activator in an experimental model of acute Cyclosporine A induced renal injury.
abstract: The use of Cyclosporine A (CsA) as rejection prophylaxis following organ transplantation is limited by its nephrotoxicity. CsA induces renal damage that is associated with tubulo-interstitial injury and parenchymal sequestration of macrophages, perpetuating pro-inflammatory processes. Furthermore, CsA exerts a diabetogenic effect by damaging pancreatic islet cell integrity. Continuous Erythropoietin Receptor Activator (CERA) was shown to mediate tissue-protective and anti-inflammatory effects in various settings of organ injury. Here, we investigated the effect of low dose CERA in a model of CsA-induced renal and pancreatic injury. Rats were exposed to medium-dose CsA for 28 days. Low-dose CERA was given to the treatment group (CERA) (n=6) once per week vs. a CsA-treated control group (CONTROL) (n=6). The effect of CERA on renal and pancreatic injuries was analyzed by organ function, histology, immunohistochemistry (CD68(+)-macrophages, insulin), ELISA (TGF-β1) and RT-PCR (TGF-β1, Osteopontin, IL-10). CsA induced functional kidney damage. Low dose CERA did not lead to improved kidney function in the treatment group. However, low dose CERA showed a trend toward upregulation of osteopontin accompanied by increased renal macrophage-infiltration and enhanced parenchymal TGF-β1 and IL-10 when compared to controls. Moreover, CERA treated animals showed amelioration of pancreatic islet cell injury. In this model of acute CsA-mediated renal injury, low dose CERA administration was associated with anti-inflammatory effects and preservation of pancreatic islet cell viability.
authors.affiliation: Division of Thoracic Surgery, University Hospital Zurich, Raemistr, 100, 8091 Zurich, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Meerwein
authors.forename: Stephan
authors.initials: S
authors.lastname: Korom
authors.forename: Stephan
authors.initials: S
authors.lastname: Arni
authors.forename: Ilhan
authors.initials: I
authors.lastname: Inci
authors.forename: Walter
authors.initials: W
authors.lastname: Weder
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jungraithmayr
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000494:pharmacology* / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006403:Hematologic Tests; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000293:injuries / Q000473:pathology / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects / Q000293:injuries / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D011092:Polyethylene Glycols / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D016572:Cyclosporine; D004921:Erythropoietin; D005947:Glucose; D016753:Interleukin-10; D053495:Osteopontin; D011092:Polyethylene Glycols; D053773:Transforming Growth Factor beta1; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C508420:continuous erythropoietin receptor activator