Systemic and sustained thioredoxin analogue prevents acute kidney injury and its-associated distant organ damage in renal ischemia reperfusion injury mice.

Abstract

The mortality of patients with acute kidney injury (AKI) remains high due to AKI associated-lung injury. An effective strategy for preventing both AKI and AKI-associated lung injury is urgently needed. Thioredoxin-1 (Trx) is a redox-active protein that possesses anti-oxidative, anti-apoptotic and anti-inflammatory properties including modulation of macrophage migration inhibitory factor (MIF), but its short half-life limits its clinical application. Therefore, we examined the preventive effect of a long-acting Trx, which is a fusion protein of albumin and Trx (HSA-Trx), against AKI and AKI-associated lung injury. Recombinant HSA-Trx was expressed using a Pichia expression system. AKI-induced lung injury mice were generated by bilateral renal ischemia reperfusion injury (IRI). HSA-Trx administration attenuated renal IRI and its-associated lung injury. Both renal and pulmonary oxidative stress were suppressed by HSA-Trx. Moreover, HSA-Trx inhibited elevations of plasma IL-6 and TNF-α level, and suppressed IL-6-CXCL1/2-mediated neutrophil infiltration into lung and TNF-α-mediated pulmonary apoptosis. Additionally, HSA-Trx suppressed renal IRI-induced MIF expression in kidney and lung. Administration of HSA-Trx resulted in a significant increase in the survival rate of renal IRI mice. Collectively, HSA-Trx could have therapeutic utility in preventing both AKI and AKI-associated lung injury as a consequence of its systemic and sustained multiple biological action.

• Authors: Kento Nishida, Hiroshi Watanabe, Masako Miyahisa, Yuto Hiramoto, Hiroto Nosaki, Rui Fujimura, Hitoshi Maeda, Masaki Otagiri, Toru Maruyama
• Journal: Scientific reports (Sci Rep) Vol. 10 Issue 1 Pg. 20635 (11 26 2020) ISSN: 2045-2322 [Electronic] England
• PMID: 33244034 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Antioxidants
• Delayed-Action Preparations
• Interleukin-6
• Macrophage Migration-Inhibitory Factors
• Reactive Oxygen Species
• Serum Albumin
• Tumor Necrosis Factor-alpha
• Thioredoxins

Topics

• Acute Kidney Injury (metabolism, prevention & control)
• Acute Lung Injury (drug therapy, metabolism)
• Animals
• Anti-Inflammatory Agents (pharmacology)
• Antioxidants (metabolism)
• Apoptosis (drug effects)
• Delayed-Action Preparations (pharmacology)
• Disease Models, Animal
• Interleukin-6 (metabolism)
• Kidney (drug effects, metabolism)
• Lung (drug effects, metabolism)
• Macrophage Migration-Inhibitory Factors (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Oxidation-Reduction (drug effects)
• Oxidative Stress (drug effects)
• Reactive Oxygen Species (metabolism)
• Reperfusion Injury (drug therapy, metabolism)
• Serum Albumin (metabolism)
• Thioredoxins (pharmacology)
• Tumor Necrosis Factor-alpha (metabolism)