Interleukin-22 as a novel therapy for trauma relevant acute kidney injury.

Abstract

Treatment for acute kidney injury (AKI) after trauma remains primarily supportive. While interleukin (IL)-22 is known to decrease cell death and stimulate regeneration in the kidney, its potential as a therapeutic in trauma-relevant AKI is unknown. IL-22:Fc is a recombinant human IL-22 protein combined with a human Fc immunoglobulin to increase serum half-life. We hypothesized that IL-22:Fc would mitigate AKI in a trauma-relevant rat model of hemorrhagic shock and resuscitation (H/R). Sprague-Dawley rats were anesthetized, and femoral arteries were cannulated. Mean arterial pressure was reduced to 40 mm Hg by withdrawing blood and kept there for 30 minutes. Animals were then resuscitated with intravenous lactated Ringer's solution to a mean arterial pressure of 60 for an additional 30 minutes. Treated animals (n = 8) received 150 μg/kg of IL-22:Fc at the start of resuscitation and compared with sham injected. Laboratories were drawn at baseline and end of resuscitation. Both groups demonstrated AKI as measured by blood urea nitrogen and serum creatinine, while treated animals had lower blood urea nitrogen and creatinine at the end of H/R. In addition, IL-22:Fc-treated animals had lower urinary albumin concentration (0.39 vs. 0.12 μg/mL, p = 0.02). Furthermore, neutrophil gelatinase-associated lipocalin levels, a marker of AKI, measured in the outer medulla were lower in treated animals. Neutrophil gelatinase-associated lipocalin levels measured in the cortex glomeruli (1,005 vs. 1,457 AU, p = 0.41) and inner medulla (5,670 vs. 5,885 AU, p = 0.16) were not different. Neutrophil gelatinase-associated lipocalin levels were higher in the tubular cortex for treated rats (2,420 vs. 3,541 AU, p = 0.02). Phosphorylated signal transducer and activator of transcription 3 levels were not higher in the kidney of treated rats. IL-22:Fc protects the kidneys after H/R and appears to act selectively on the outer medulla. This beneficial effect does not appear to be mediated by signal transducer and activator of transcription 3, as shown in other organ systems. IL-22:Fc may be a novel therapy for AKI in trauma patients.