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Abstract: SA-PO126

The Progression of AKI to Chronic Tubulointerstitial Fibrosis Was Ameliorated in IL-18 Knockout Mice After Folic Acid Induction

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Luan, Junjun, The Affiliated Shengjing Hospital of China Medical School, Shenyang/China, LiaoNing, China
  • Fu, Jingqi, Chinese Medical University, Shenyang, LIAONING, China
  • Pi, Jingbo, Chinese Medical University, Shenyang, LIAONING, China
  • Li, Detian, The Affiliated Shengjing Hospital of China Medical School, Shenyang/China, LiaoNing, China
  • Zhou, Hua, The Affiliated Shengjing Hospital of China Medical School, Shenyang/China, LiaoNing, China
Background

Folic acid (FA)-induced acute kidney injury (AKI) can proceed to chronic tubulointerstitial fibrosis (TIF) in mice. This is clinical relevant animal model of AKI to latent TIF. The mechanisms of the progression still remain unclear. We aim to investigate the role of interleukin (IL)-18, a cytokine secreted by macrophages and T cells, in the progression from AKI to TIF induced by FA and its corresponding mechanisms.

Methods

We first explored time course of renal injury and IL-18 expression in Il18+/+ mice at day 2, 14, and 30 after 250mg/ kg of FA intraperitoneal injection. Then we compared the acute necroptosis indicated by receptor-interacting serine/threonine-protein kinase1 (RIPK1), RIPK3, and phosphorylation of mixed lineage kinase domain like pseudokinase (p-MLKL); transdifferentiation marked by IL-11, transforming growth factor β1, vimentin, and connective tissue growth factor; renal fibrosis expressed with α-smooth muscle activating protein and collagen type I as well as inflammatory response including cytokines, M1 and M2 macrophages, and T lymphocytes infiltration in Il18+/+ and Il18−/− mice after FA administration at each experimental time point.

Results

In Il18+/+mice following FA injection, renal IL-18 and serum interferon-γ progressively increased accompanied with the progression from AKI to TIF. In addition, biomarkers of necroptosis on day 2, transdifferentiation on day 14, and tubulointerstitial fibrosis on day 30, M1 macrophages on day 14, and M2 macrophages on day 30 were peaked respectively at the different time points after FA injection. In Il18−/− mice, traditional acute and chronic renal damage, necroptosis, transdifferentiation, and renal fibrosis were all attenuated. Importantly, IL-18 deficiency decreased infiltration of M1 macrophages and its secreted cytokines on day 2 and day 14, reduced the infiltrated M2 macrophages and T cells as well as their related inflammatory responses at each time points from day 2 to 30 after FA.

Conclusion

IL-18 deficiency suppressed renal tubular damage, necroptosis, transdifferentiation, and fibrosis in FA-induced AKI to TIF. The renal protective role of IL-18 deletion in this progression might be mediated by inhibition of cytokines and the infiltrated M1, M2 macrophages, and T cells as well as the macrophage transformation from M1 to M2 types.

Funding

  • Government Support - Non-U.S.