title: Hepatocyte growth factor prevents the development of chronic allograft nephropathy in rats.
abstract: Long-term renal isografts in humans and laboratory animals exhibit features similar to those of chronic allograft nephropathy (CAN), indicating that antigen-independent factors, such as acute renal ischemia, are likely to be involved in the development of CAN. Hepatocyte growth factor (HGF) has been demonstrated to play a renotropic role in renal regeneration and protection from acute ischemic injury. This study was thus conducted to investigate the effect of HGF on the development of CAN, using an established rat model. HGF was administered daily (100 microg/d, intravenously) for 4 wk after engraftment. Control animals received saline solution. Allografts from control animals exhibited early evidence of severe structural collapse and necrotic cell death in the proximal tubules and outer medulla, with mononuclear cell infiltration, within 1 wk after engraftment. This was followed by sequential upregulation of adhesion molecules and cytokines, accompanied by dense macrophage infiltration. Fibrogenic events, as indicated by marked increases in transforming growth factor-beta1 expression and the accumulation of smooth muscle alpha-actin, occurred during the same period. Control animals ultimately developed features typical of CAN, with functional deterioration and severe histologic changes; a survival rate of 50.6% by 32 wk was observed. In contrast, remarkably little early injury and no late fibrogenic events were observed for the HGF-treated group. All treated animals survived, with well preserved graft function, during the 32-wk follow-up period. These results indicate that renal protection and recovery from early allograft injury with HGF treatment greatly contribute to a reduction of susceptibility to the subsequent development of CAN in a rat model. The potential application of HGF in the prevention of CAN warrants further attention.
authors.affiliation: Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Haruhito
authors.initials: H
authors.lastname: Azuma
authors.affiliation: Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Takahara
authors.affiliation: Division of Biochemistry, Biomedical Research Center, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Kunio
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Naotsugu
authors.initials: N
authors.lastname: Ichimaru
authors.affiliation: Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Jing Ding
authors.initials: JD
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Moriyama
authors.affiliation: Laboratory of Immunogenetics and Transplantation, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Waaga
authors.affiliation: Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Kitamura
authors.affiliation: Department of Anatomy and Biology, Osaka Medical College, Osaka, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Otsuki
authors.affiliation: Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Okuyama
authors.affiliation: Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Katsuoka
authors.affiliation: Laboratory of Immunogenetics and Transplantation, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Anil
authors.initials: A
authors.lastname: Chandraker
authors.affiliation: Laboratory of Immunogenetics and Transplantation, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
authors.affiliation: Division of Biochemistry, Biomedical Research Center, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D053938:DNA Fragmentation; D004587:Electrophoresis, Agar Gel; D006084:Graft Rejection / Q000473:pathology* / Q000517:prevention & control*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D016030:Kidney Transplantation; D008297:Male; D008854:Microscopy, Electron; D012313:RNA / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D012313:RNA; D017228:Hepatocyte Growth Factor