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.
Highlights
The mortality of patients with acute kidney injury (AKI) remains high due to AKI associated-lung injury
The mouse model of AKI-associated lung injury was induced by renal ischemia reperfusion injury (IRI) where both renal pedicles were clamped for 60 min (Supplemental Fig. 1A)
We investigated whether human serum albumin (HSA)-Trx attenuates renal IRI-induced lung injury via suppressing IL-6–CXCL1/2-mediated neutrophil infiltration into lung
Summary
The mortality of patients with acute kidney injury (AKI) remains high due to AKI associated-lung injury. Three cascades of events leading from AKI to lung injury have been reported: (1) IL-6-mediated neutrophil infiltration into lung[7,8], (2) TNF-α-mediated pulmonary a poptosis[9,10,11], and (3) an increase in plasma cytokine levels derived from extra-renal organs such as liver[12,13,14]. After AKI, extra-renal tissue such as liver produces inflammatory cytokines, which contribute to their elevation in the plasma thereby further accelerating lung injury via cytokine-mediated cascades Based on this evidence in which oxidative stress, apoptosis and inflammation are strongly associated with the development of AKI and its complications, a prophylactic agent is needed to exert systemic and sustained anti-oxidative, anti-apoptotic and anti-inflammatory actions. Due of its systemic and sustained multiple biological effects, we reasoned that HSA-Trx may prevent both AKI and AKI-associated lung injury
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