Immunosuppression with 4SC-101, a novel inhibitor of dihydroorotate dehydrogenase, in a rat model of renal transplantation

K. Rusai, Christoph Schmaderer, Marcus Baumann, Stefan Chmielewski, Ágnes Prókai, Eva Kis, Attila J. Szabó, Johann Leban, Robert Doblhofer, Aldo Ammendola, Jens Lutz, Uwe Heemann

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Abstract

Background: 4SC-101 is a novel dihydroorotate dehydrogenase inhibitor and a blocker of interleukin (IL)-17 secretion with beneficial effects in experimental lupus and inflammatory bowel disease. Its immunomodulatory effect on acute kidney rejection is not known; therefore, in this study, the impact of 4SC-101 was examined in a rat model of acute kidney rejection. Methods: The kidneys of Brown-Norway rats were orthotopically transplanted into bilaterally nephrectomized Lewis recipients. Allograft recipients were administered with 4SC-101 at dosages of 4, 20, or 60 mg/kg per day, and survival was assessed. In the second setting, the animals were harvested 3 or 5 days after transplantation (Tx), and graft histologic diagnosis was determined. The effects of 4SC-101 on impaired renal function were examined in a model of 5/6 nephrectomy in Lewis rats. Results: The recipients treated with 20-mg/kg 4SC-101 showed prolonged survival compared with placebo-treated animals (mean±SEM, 24±9.3 vs. 5.4±3 days), paralleled by less severe histologic features of acute kidney rejection such as interstitial/perivascular infiltration and tubulitis 3 and 5 days after Tx, and a lower level of IL-17 messenger RNA 5 days after Tx compared with the placebo-treated animals. In the 5/6 nephrectomy model, 20-mg/kg 4SC-101 reduced proteinuria, glomerulosclerosis, and fibrosis with decreased IL-17 messenger RNA expression. Conclusions: 4SC-101 prolongs survival after Tx, paralleled by amelioration of histologic signs of acute rejection. Furthermore, it showed no worsening effects on kidney function in a remnant kidney model and even slowed the progression of proteinuria and kidney fibrosis. Therefore, 4SC-101 might be a promising pharmaceutical agent in Tx medicine for further investigations.

Original languageEnglish
Pages (from-to)1101-1107
Number of pages7
JournalTransplantation
Volume93
Issue number11
DOIs
Publication statusPublished - Jun 15 2012

Fingerprint

Kidney Transplantation
Immunosuppression
Kidney
Interleukin-17
Nephrectomy
Proteinuria
Fibrosis
Placebos
Messenger RNA
vidofludimus
dihydroorotate dehydrogenase
Inflammatory Bowel Diseases
Allografts
Transplantation
Medicine
Transplants
Pharmaceutical Preparations

Keywords

  • Acute rejection
  • Kidney
  • Novel dihydroorotate dehydrogenase inhibitor

ASJC Scopus subject areas

  • Transplantation

Cite this

Immunosuppression with 4SC-101, a novel inhibitor of dihydroorotate dehydrogenase, in a rat model of renal transplantation. / Rusai, K.; Schmaderer, Christoph; Baumann, Marcus; Chmielewski, Stefan; Prókai, Ágnes; Kis, Eva; Szabó, Attila J.; Leban, Johann; Doblhofer, Robert; Ammendola, Aldo; Lutz, Jens; Heemann, Uwe.

In: Transplantation, Vol. 93, No. 11, 15.06.2012, p. 1101-1107.

Research output: Contribution to journalArticle

Rusai, K, Schmaderer, C, Baumann, M, Chmielewski, S, Prókai, Á, Kis, E, Szabó, AJ, Leban, J, Doblhofer, R, Ammendola, A, Lutz, J & Heemann, U 2012, 'Immunosuppression with 4SC-101, a novel inhibitor of dihydroorotate dehydrogenase, in a rat model of renal transplantation', Transplantation, vol. 93, no. 11, pp. 1101-1107. https://doi.org/10.1097/TP.0b013e31824fd861
Rusai, K. ; Schmaderer, Christoph ; Baumann, Marcus ; Chmielewski, Stefan ; Prókai, Ágnes ; Kis, Eva ; Szabó, Attila J. ; Leban, Johann ; Doblhofer, Robert ; Ammendola, Aldo ; Lutz, Jens ; Heemann, Uwe. / Immunosuppression with 4SC-101, a novel inhibitor of dihydroorotate dehydrogenase, in a rat model of renal transplantation. In: Transplantation. 2012 ; Vol. 93, No. 11. pp. 1101-1107.
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