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Kidney Week

Abstract: FR-OR030

Long-Acting Thioredoxin Prevents AKI to CKD Transition via Its Anti-Oxidative and Anti-Inflammatory Action

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Watanabe, Hiroshi, Department of Biopharmaceutics, School of Pharmacy, Kumamoto University, Kumamoto-shi, Japan
  • Nishida, Kento, Department of Biopharmaceutics, School of Pharmacy, Kumamoto University, Kumamoto-shi, Japan
  • Fujimura, Rui, Department of Biopharmaceutics, School of Pharmacy, Kumamoto University, Kumamoto-shi, Japan
  • Maruyama, Toru, Department of Biopharmaceutics, School of Pharmacy, Kumamoto University, Kumamoto-shi, Japan
Background

Renal fibrosis is common finding in CKD and is induced by the sustained oxidative stress and inflammation after AKI. Therefore, an effective strategy is highly desirable for preventing AKI to CKD transition. 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 to CKD transition.

Methods

Recombinant HSA-Trx was expressed using Pichia expression system. AKI to CKD transition model mice were generated by renal ischemia-reperfusion (IR).

Results

From day 1 to day 14 after renal IR, recovery of renal function and body weight were accelerated by HSA-Trx administration. HSA-Trx ameliorated excessive extracellular matrix deposition and the increase in hydroxyproline content and Col1a2 mRNA expression in the kidney on day 14 after renal IR. HSA-Trx also suppressed epithelial-endothelial transition, is known as the process of fibrosis progression. To elucidate the suppressive mechanism of HSA-Trx on AKI to CKD transition, we examined at the early phase of fibrogenesis (day 7) after renal IR. HSA-Trx treatment ameliorated renal histological alterations and decreased the increase in renal mRNA expression of Kim-1 and Sox9, which is injury marker and regeneration marker in renal tubule, respectively. In addition, the increase in oxidative stress, pro-inflammatory cytokine expression, and the number of macrophages in the kidney of PBS-treated mice were suppressed by HSA-Trx. Similarly, HSA-Trx treatment inhibited G2/M cell cycle arrest and apoptosis in renal tubule cells, which are involved in CKD progression. While renal Trx protein level were significantly decreased by renal IR, HSA-Trx suppressed the decrease in renal Trx protein level, suggesting that HSA-Trx exerts renoprotective effect partially due to preserve renal Trx protein level.

Conclusion

HSA-Trx has potential for use in the treatment of AKI to CKD transitionvia its extended effects of modulating oxidative stress and inflammation.