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Kidney Week

Abstract: FR-PO848

Dimethyl Fumarate Ameliorates Tacrolimus-Induced Nephrotoxicity in Rats

Session Information

  • Transplantation: Basic
    October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Transplantation

  • 1801 Transplantation: Basic

Authors

  • Shimomura, Akihiro, University of California, Irvine, Orange, California, United States
  • Li, Shiri, University of California, Irvine, Orange, California, United States
  • Dafoe, Donald Cameron, University of California, Irvine, Orange, California, United States
  • Ichii, Hirohito, University of California, Irvine, Orange, California, United States
Background

Tacrolimus (TAC) is an important maintenance immunosuppressive drug that is widely used for organ transplant. However, patients treated with TAC are at high risk of developing organ injuries such as kidney and pancreas, especially kidney is more susceptible to TAC. TAC causes renal dysfunction or failure not only on donor kidneys but also on native kidneys. The incidence is 52%, 40% and 59% in patients after kidney, liver and heart transplants, respectively. Despite the tremendous efforts to reduce TAC-induced kidney injury, satisfactory therapies have not been established because the exact pathogenesis has remained unclear. There are increasing evidences that oxidative stress is involved in both TAC-induced kidney and pancreas injuries. Dimethyl fumarate (DMF), which has recently been approved by FDA for the treatment of relapsing forms of multiple sclerosis (MS) and relapsing-remitting MS patient, is a modifier of the nuclear factor-2-keap1 pathway that induces antioxidative and antiapoptotic effects. In the present study, we investigated the effects of DMF on TAC-induced kidney and pancreas injuries.

Methods

Male Sprague-Dawley rats at 9 weeks of age were divided randomly into four groups; low-salt (LS) diet (group LS), LS+DMF (group DMF), LS+TAC (group TAC), or LS+TAC+DMF (group TAC+DMF). DMF at a dose of 50 mg/kg・BW or vehicle was gavaged once a day. TAC at a dose of 1.5 mg/kg・BW or vehicle was subcutaneously injected once a day.

Results

At 15 weeks of age, significantly elevated levels of serum creatinine and urea nitrogen were detected in group TAC. Group TAC+DMF showed significantly lower levels of them than group TAC. Both Masson’s Trichrome staining and immunohistochemical collagen1 staining of rat kidney showed consistent results with renal function. On the other hand, intraperitoneal glucose tolerance test, HOMA-IR and HOMA-β showed significantly impaired glucose tolerance and β cell function in group TAC, which could not be improved by DMF.

Conclusion

DMF ameliorated kidney injury but not pancreas injury in the TAC-induced rat model. This provides a novel approach for preventing TAC-induced nephrotoxicity in patients after organ transplant. Our data also indicates that TAC-induced kidney and pancreas injuries may have different pathogenic mechanisms. We expect to further investigate the pathogenic mechanisms of TAC-induced organ injuries.