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Kidney Week

Abstract: TH-PO466

Knockout of Interleukin-36 Receptor Ameliorates AKI-to-CKD Transition via Prevention of Fibrosis and Inflammasome

Session Information

  • CKD: Mechanisms - I
    November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Yuji, Kadowaki, kochi medical school, Nankoku-city, Japan
  • Terada, Yoshio, Kochi Medical School, Nankoku-city, Japan
  • Fujimoto, Shimpei, Kochi University, Nankoku, Japan
  • Taniguchi, Yoshinori, Kochi University, Nankoku, Japan
  • Ogasawara, Masami, Kochi university, Nankokushi, Japan
  • Nishikawa, Hirofumi, Kochi University, Nankoku, Japan
  • Horino, Taro, Kochi Medical School, Kochi University, Kochi, Japan
  • Inotani, Satoshi, Kochi university, Nankokushi, 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 fibrosis during AKI to CKD transition. We examined IL-36 function using mice AKI to CKD models and clinical samples.

Methods

We evaluated IL-36 function in two models of AKI to CKD transition by using IL-36R knockout (KO) and wild-type (WT) mice. First model, left renal ischemia was performed for 35min and right kidney was removed 21days later, and left kidney analyses at 28 days (IRI). Second model, we used aristolochic acid toxic nephropathy (AAN) in mice at 28 days. We evaluate the renal function and histological analysis of KO and WT mice in both models. Fibrotic changes and inflammasome were evaluated by RT-PCR, Western blot analysis. Immunohistologial analysis of collagen type IV, CTGF, and Masson trichrome staining were performed. In clinical study, we performed immunohistological examination of IL-36α in AKI to CKD patients renal biopsy sample.

Results

IL-36R was found to be expressed in the kidney mainly in proximal tubules in WT mice. IL-36R KO mice had significantly lower Cr and BUN at 28 days compared to WT mice in both models. Immunohistological examination showed mild tubular injury and fibrotic change in IL-36R KO mice compared to WT mice in both models. IL-36α/β/γ levels were increased after IRI and AAN, and IL-36α was expressed in lymphocytes and renal tubular cells. Immunohistologial analysis of collagen type IV and CTGF, and Masson trichrome staining revealed that massive fibrotic changes were observed in WT mice compared to KO mice. Protein expression of collagen type IV, CTGF, and inflammasome proteins(NLRP3, IL-1b, caspase 1) were also increased in WT mice compared to KO mice. IL-36α staining in renal-biopsy samples of AKI to CKD patients was enhanced.

Conclusion

Our results demonstrate that IL-36α is up-regulated in renal tissues in both mouse and human AKI to CKD transition, and that IL-36α stimulates collagen type IV, CTGF, and inflammasome in AKI to CKD transition models. Thus, IL-36α/IL-36R blockage could serve as a potential therapeutic target in AKI to CKD transition.