Abstract: TH-PO231

Dimethyl Fumarate Attenuates Renal Ischemia/Reperfusion Injury

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic

Authors

  • Li, Yingchuan, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
  • Li, Junhui, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
  • Xue, Hong, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Wang, Feng, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
  • Lombard, Julian H., Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Geurts, Aron M., Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Usa, Kristie, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Wang, Niansong, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
  • Liang, Mingyu, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
Background

Fumarate is an intermediary in the tricarboxylic acid cycle and can activate NRF2 and HIF-1a. Emerging evidence suggests fumarate might be involved in ischemia-reperfusion injury (IRI). It remains unclear whether fumarate is protective against acute kidney injury (AKI) resulting from renal IRI and what mechanisms might be involved.

Methods

Male SD or Nrf2-/- rats (~250g) were anaesthetized with ketamine. Sham operation (controls) or bilateral renal artery occlusion for 30 min followed by reperfusion (IRI) were performed. For pre-IRI treatment, dimethyl fumarate (DMF, 30mg/Kg), a fumarate precursor, or Vehicle was administered via intraperitoneal injection twice daily for 5 days before surgery. For post-ischemia treatment, DMF (30mg/Kg) or Vehicle was administrated at the time of 0 and 3 hours after reperfusion. Serum was collected 6 h or 24 h post-reperfusion and kidney collected 24 h post-reperfusion for analysis of renal function and kidney injury.

Results

Pre-treatment with DMF for 5 days attenuated subsequent renal IRI in rats. Serum creatinine (Scr) was 1.05±0.26 mg/dl and 1.42±0.42 mg/dl in DMF- and vehicle-treated rats, respectively (n=11, p<0.05). Tubular injury score (TIS) was 2.76±0.64 and 4.00±0.88 in the two groups (n=5, p<0.05). The attenuation of renal injury was associated with up-regulation of mRNA expression of HIF-1a, NRF2 and their target genes Hmox1 and Nqo1 in kidney tissue. However, the effect of DMF pre-treatment on renal IRI was preserved in Nrf2-/- rats. Post-ischemia Treatment with DMF also significantly attenuated renal IRI. Scr was 1.08±0.46 mg/dl and 1.76±0.74 mg/dl in DMF- and vehicle-treated rats, respectively (n=8, p<0.05). TIS was 2.82±0.71 and 4.06±0.92 in the two groups (n=5, p<0.05). The post-ischemia treatment with DMF resulted in up-regulation of NRF2, Hmox1 and Nqo1, but not HIF-1a. The protective effect of post-ischemia treatment with DMF on renal IRI was significantly attenuated in Nrf2-/- rats.

Conclusion

These results suggest fumarate could have preventive as well as therapeutic effects on AKI induced by IRI. The therapeutic, but not preventive, effect of fumarate depends on the presence of NRF2.

Funding

  • NIDDK Support