Recombinant human hepatocyte growth factor (HGF), but not rat HGF, elicits glomerular injury and albuminuria in normal rats via an immune complex-dependent mechanism.
1. Hepatocyte growth factor (HGF) has the therapeutic potential to improve renal fibrosis and proteinuria in rodents with chronic kidney disease. In contrast, long-term administration of human HGF to normal rats reportedly elicits proteinuria. Thus, the role of HGF during proteinuria remains contentious. The aim of the present study was to demonstrate that human HGF is antigenic to rodents and that immune complex formation causes proteinuria. 2. We administered either human or rat HGF to normal rats for 28 days. Albuminuria was evaluated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. The renal phenotypes of the two HGF treatments were examined using histological techniques. 3. Administration of human HGF (1 mg/kg per day, i.v.) to rats led to severe albuminuria and glomerular hypertrophy in association with increased blood levels of anti-human HGF IgG and IgG deposition in mesangial areas. Furthermore, an immune complex between human HGF and anti-human HGF IgG stimulated the production of proteinuric cytokines (including transforming growth factor-β) in rat cultured mesangial cells. In contrast, treatment of healthy rats with rat HGF for 4 weeks caused neither mesangial IgG deposition nor elevated anti-HGF IgG in the blood. Overall, rat HGF did not provoke albuminuria. 4. We conclude that human HGF produces pseudotoxic effects in normal rat kidneys via an immune complex-mediated pathway, whereas syngenic HGF is safe due to less deposition of glomerular IgG. Our results affirm the safety of the repeated use of syngenic HGF for the treatment of chronic organ diseases, such as renal fibrosis and liver cirrhosis.
Division of Molecular Regenerative Medicine, Department of Biochemistry and Molecular Biology, Osaka University Graduate School of Medicine, OsakaSaito Laboratory, Research & Development, Kringle Pharma Inc., IbarakiKringle Pharma Joint Research Division for Regenerative Drug Discovery, Center for Advanced Science and Innovation, Osaka University, SuitaDivision of Tumor Dynamics and Regulation, Kanazawa University Cancer Research Institute, Kanazawa, Japan.
Shinya
S
Mizuno
Fumie
F
Ikebuchi
Kazuhiro
K
Fukuta
Takashi
T
Kato
Kunio
K
Matsumoto
Kiichi
K
Adachi
Tetsushi
T
Abe
Toshikazu
T
Nakamura
D000419:Albuminuria / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism; D005920:Glomerular Mesangium / Q000187:drug effects / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000009:adverse effects* / Q000494:pharmacology; D006801:Humans; D006984:Hypertrophy / Q000139:chemically induced / Q000378:metabolism; D007074:Immunoglobulin G / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000009:adverse effects / Q000494:pharmacology
D000936:Antigen-Antibody Complex; C066855:HGF protein, human; D007074:Immunoglobulin G; D011994:Recombinant Proteins; D017228:Hepatocyte Growth Factor