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Kidney Week

Abstract: FR-PO078

Knockout of Interleukin-36 Receptor Protects Against Renal Ischemia-Reperfusion Injury through Reduction of Proinflammatory Cytokines

Session Information

  • AKI Clinical: Predictors
    November 03, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Acute Kidney Injury

  • 003 AKI: Clinical and Translational

Authors

  • Nishikawa, Hirofumi, Kochi University, Nankoku, Japan
  • Eguchi, Tomohiro, Kochi University, Nankoku, Japan
  • Ogasawara, Masami, Kochi University, Nankoku, Japan
  • Matsumoto, Tatsuki, Kochi University, Nankoku, Japan
  • Ode, Kazu Hamada, Kochi University, Nankoku, Japan
  • Shimamura, Yoshiko, Kochi University, Nankoku, Japan
  • Inoue, Kosuke, Kochi University, Nankoku, Japan
  • Taniguchi, Yoshinori, Kochi University, Nankoku, Japan
  • Horino, Taro, Kochi University, Nankoku, Japan
  • Terada, Yoshio, Kochi University, Nankoku, Japan
Background

IL-36, a newly named member of the IL-1 cytokine family, includes 3 isoforms, IL-36α, IL-36β, and IL-36γ, all of which bind to a heterodimer containing IL-36 receptor (IL-36R). Little is known about the role of the IL-36 axis in acute kidney injury (AKI) pathogenesis. We examined IL-36 function using mice AKI model and clinical samples.

Methods

We evaluated IL-36 function in the bilateral renal ischemia-reperfusion injury (IRI) AKI model by using IL-36R knockout (KO) and wild-type (WT) mice. We at first evaluate the localization of IL-36R in WT mice kidney by confocal microscopy. The effects of IL-36α on NF-kB and Erk activities were examined in primary cultured renal tubular cells. In clinical study, we measured urine IL-36α in AKI patients, and immunohistological examination of IL-36α in AKI and minimal change renal biopsy sample.

Results

IL-36R was found to be expressed in the kidney mainly in proximal tubules. IL-36R KO mice had significantly lower PCr (0.41+0.12 versus 1.08 + 0.21 mg/dl), BUN (65.3+14.8 versus 158+31.5 mg/dl) and IL-6 (24.3 + 5.7 versus 39.6+7.9 pg/ml) at 24h after IRI compared to WT mice. Immunohistological examination showed mild tubular injury in IL-36R KO mice. IL-36α/β/γ levels were increased after IRI, and IL-36α was expressed in lymphocytes and renal tubular cells, but post-IRI mRNA levels of IL-6 and TNF-α were low in IL-36R KO mice. We found that IL-36R expression in radioresistant renal tubule-resident cells, but not hematopoietic bone marrow-derived cells, was essential for IRI pathology by bone marrow chimeras experiments. In primary cultures of renal tubular epithelial cells, IL-36α treatment upregulated NF-κB activity and Erk phosphorylation. Notably, in AKI patients, urine IL-36α levels were increased, and IL-36α staining in renal-biopsy samples was enhanced.

Conclusion

Our results demonstrate that IL-36α is upregulated in renal tissues in both mouse and human AKI, and that IL-36α stimulates NF-κB and Erk pathways and might induce cytokines such as IL-6 and TNF-α in AKI. Thus, IL-36α/IL-36R blockage could serve as a potential therapeutic target in AKI.