Abstract: TH-PO083
Knockout of Interleukin-36 Receptor Prevents Fibrosis in Mice Models of AKI-to-CKD Progression
Session Information
- AKI: Inflammation, New Technologies, Omics
October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Masami, Ogasawara, Kochi University, Nankoku, Japan
- Terada, Yoshio, Kochi University, Nankoku, Japan
- Nishikawa, Hirofumi, Kochi University, Nankoku, Japan
- Taniguchi, Yoshinori, 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 fibrosis during AKI to CKD progression. 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 progression 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 were evaluated by RT-PCR, Western blot analysis, and immunohistologial analysis of collagen type IV, CTGF, and Masson trichrome staining. In clinical study, we performed immunohistological examination of IL-36α in AKI to CKD patients and minimal change 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 in both models. Protein expression of collagen type IV and CTGF were also increased in WT mice compared to KO mice. Notably, 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 and CTGF in AKI to CKD transition models. Thus, IL-36α/IL-36R blockage could serve as a potential therapeutic target in AKI to CKD transition.