13-cis retinoic acid inhibits development and progression of chronic allograft nephropathy.
Chronic allograft nephropathy is characterized by chronic inflammation and fibrosis. Because retinoids exhibit anti-proliferative, anti-inflammatory, and anti-fibrotic functions, the effects of low and high doses of 13-cis-retinoic acid (13cRA) were studied in a chronic Fisher344-->Lewis transplantation model. In 13cRA animals, independent of dose (2 or 20 mg/kg body weight/day) and start (0 or 14 days after transplantation) of 13cRA administration, serum creatinine was significantly lower and chronic rejection damage was dramatically reduced, including subendothelial fibrosis of preglomerular vessels and chronic tubulointerstitial damage. The number of infiltrating mononuclear cells and their proliferative activity were significantly diminished. The mRNA expression of chemokines (MCP-1/CCL2, MIP-1alpha/CCL3, IP-10/CXCL10, RANTES/CCL5) and proteins associated with fibrosis (plasminogen activator inhibitor-1, transforming growth factor-beta1, and collagens I and III) were strikingly lower in treated allografts. In vitro, activated peritoneal macrophages of 13cRA-treated rats showed a pronounced decrease in protein secretion of inflammatory cytokines (eg, tumor necrosis factor-alpha, interleukin-6). The suppression of the proinflammatory chemokine RANTES/CCL5 x 13cRA in fibroblasts could be mapped to a promoter module comprising IRF-1 and nuclear factor-kappaB binding elements, but direct binding of retinoid receptors to promoter elements could be excluded. In summary, 13cRA acted as a potent immunosuppressive and anti-fibrotic agent able to prevent and inhibit progression of chronic allograft nephropathy.
Department of Cellular and Molecular Pathology, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Judith
J
Adams
Eva
E
Kiss
Ana B V
AB
Arroyo
Mahnaz
M
Bonrouhi
Qiang
Q
Sun
Zhen
Z
Li
Norbert
N
Gretz
Anna
A
Schnitger
Christos C
CC
Zouboulis
Manfred
M
Wiesel
Jürgen
J
Wagner
Peter J
PJ
Nelson
Hermann-Josef
HJ
Gröne
D000818:Animals; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002908:Chronic Disease; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D015474:Isotretinoin / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D016030:Kidney Transplantation; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014184:Transplantation, Homologous
D018925:Chemokines; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D003404:Creatinine; D015474:Isotretinoin