Abstract: TH-PO309

Systemic Effects of Long-Acting Albumin-Thioredoxin Fusion Protein against Distant Organ Injury Following AKI

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic

Authors

  • Nishida, Kento, Department of Biopharmaceutics, School of Pharmacy, Kumamoto University, Kumamoto-shi, Japan
  • Watanabe, Hiroshi, Department of Biopharmaceutics, School of Pharmacy, Kumamoto University, Kumamoto-shi, Japan
  • Fukagawa, Masafumi, Tokai University School of Medicine, Isehara, Kanagawa, Japan
  • Maruyama, Toru, Department of Biopharmaceutics, School of Pharmacy, Kumamoto University, Kumamoto-shi, Japan
Background

The high mortality of acute kidney injury (AKI) is associated with distant organ injury such as lung and liver injury. Therefore, an effective strategy is highly desirable for preventing AKI-associated distant organ injury induced by increasing oxidative stress and inflammatory response. Thioredoxin-1 (Trx) is a redox-active protein that has anti-oxidative and anti-inflammatory properties. Although, Trx has great potential for use as a therapeutic agent against several types of oxidative stress-related diseases, its short half-life limits its clinical application. To overcome this problem, we produced a recombinant fusion protein that is comprised of human serum albumin and Trx (HSA-Trx), and examined its preventive effect against AKI-induced distant organ injury.

Methods

Recombinant HSA-Trx was expressed using Pichia expression system. AKI-induced distant organ injury mice were produced by renal ischemia reperfusion injury (IRI).

Results

A pharmacokinetic study of HSA-Trx or Trx in mice showed that the plasma retention of Trx was markedly increased by fusion with HSA. HSA-Trx treatment attenuated the renal IRI-induced decline in renal function and histological alterations. HSA-Trx also attenuated not only lung injury, including increased neutrophil infiltration, vascular hyper-permeability and alveolar expansion, but also liver injury, including elevated aspartate aminotransferase and alanine aminotransferase following renal IRI. In plasma, the elevation of inflammatory cytokine was suppressed by HSA-Trx treatment. In kidney, lung and liver, HSA-Trx suppressed the number of apoptosis-positive cells, cytokine and chemokine mRNA expression and oxidative stress. The administration of HSA-Trx resulted in a significant increase in survival rate, with 55% of the mice being alive at 7 days after the renal IRI.

Conclusion

HSA-Trx has potential for use in the treatment of AKI-induced distant organ injury via its extended effects of modulating oxidative stress and inflammation.