Abstract
Background: Most of the ischemia-reperfusion injury (IR-I) occurs during reperfusion and is mediated by the immune system. In this study we determined whether immunomodulation with hyper-Interleukin-6 (a recombinant designer cytokine composed of interleukin-6 linked to its soluble receptor) is protective against IR-I in mice kidneys.Methods: Hyper-Interleukin-6 (HIL-6) was administered by in vivo plasmid DNA transfection to 10 male mice. Twenty-four hours later, unilateral nephrectomy was done. IR-I immediately followed by closure of the remaining kidney vascular pedicle for 40 min. Seven mice transfected with non-coding control plasmid served as the control group. The functional and morphological effects of IR-I and its effect on mice longevity were explored. This was done by serial blood tests and by histopathology done upon sacrifice of the animals at post-operative day 7.Findings: Mice pretreated with HIL-6 had a mean creatinine level at post-operative day 1 of 35.45 ± 4.03 μmol/l and mean Urea level was 14.18 ± 2.69 mmol/l, whereas mean creatinine was 89.33 ± 69.27 μmol/l (P = 0.025), and mean urea was 38.17 ± 20.77 mmol/l (P = 0.0024) in the control group. Histological changes in the control group included inflammatory infiltration, tubular damage, and architectural distortion. These were not seen in the treatment group. Seven days post-operatively the survival rate of treated mice was 100% compared to 50% in the control group (P = 0.015).Interpretation: In this single kidney mouse model, pretreatment with HIL-6 administration effectively protected against IR-I both morphologically and functionally. Further studies are needed to better understand the mechanism and feasibility of using this immunomodulator.
Highlights
Renal cancer accounts for about 5% of all newly diagnosed malignancies in men and 3% in women [1]
As we have shown previously, IL-6 trans-signaling by the recombinant IL6/sIL-6R fusion protein, Hyper-IL-6 (HIL-6) [18] can strongly upregulate STAT3 phosphorylation in the kidney and largely prevent reactive oxygen species (ROS)-mediated acute kidney injury (AKI) [10, 19]
From the Trial A (n = 20) we found out that by increasing ischemia times from 16 to 40 min the mice showed proportionally increasing renal failure manifested by elevated creatinine and BUN levels on post-operative day 1 (Figures 1A,B)
Summary
Renal cancer accounts for about 5% of all newly diagnosed malignancies in men and 3% in women [1]. Most of the increase is in small stage I tumors while the incidence of stages II, III, and IV disease is decreasing [3] This change is accompanied by a steady improvement in patients longevity raising the importance of renal function preservation while caring for these patients [4]. About 25–30% of the patients with small renal masses are affected by some degree of chronic kidney disease (CKD) even before surgery. This is due to commonly shared risk factors including older age, diabetes mellitus, and hypertension [5]. In this study we determined whether immunomodulation with hyper-Interleukin-6 (a recombinant designer cytokine composed of interleukin-6 linked to its soluble receptor) is protective against IR-I in mice kidneys
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