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(American Journal of Pathology. 2005;167:285-298.)
© 2005 American Society for Investigative Pathology

13-cis Retinoic Acid Inhibits Development and Progression of Chronic Allograft Nephropathy

Judith Adams*{dagger}, Eva Kiss*, Ana B.V. Arroyo{ddagger}, Mahnaz Bonrouhi*, Qiang Sun*, Zhen Li*, Norbert Gretz§, Anna Schnitger, Christos C. Zouboulis, Manfred Wiesel{dagger}, Jürgen Wagner{dagger}, Peter J. Nelson{ddagger} and Hermann-Josef Gröne*

From the Department of Cellular and Molecular Pathology,* German Cancer Research Center, Heidelberg; the Departments of Urology and Nephrology,{dagger} University Hospital, Heidelberg; Clinic of Internal Medicine,{ddagger} Biochemistry Group, University of Munich, Munich; Medical Research Center,§ Klinikum Mannheim, University of Heidelberg, Heidelberg; and the Department of Dermatology, Charite University Medicine Campus Benjamin Franklin, Berlin, Germany

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-1{alpha}/CCL3, IP-10/CXCL10, RANTES/CCL5) and proteins associated with fibrosis (plasminogen activator inhibitor-1, transforming growth factor-ß1, 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-{kappa}B 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.




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