Bin Sun1, Hui Wang2, Lu Zhang3, Xiaofan Yang4, Mingshun Zhang4, Xingxing Zhu4, Xiaohui Ji4, Huijuan Wang5. 1. The First Affiliated Hospital of Nanjing Medical University, Division of Nephrology, Department of Internal Medicine, Nanjing, Jiangsu, China. 2. Jiangsu Jiankang Vocational College, Nanjing, Jiangsu, China. 3. Nanjing Red Cross Blood Center, Nanjing, Jiangsu, China. 4. Nanjing Medical University, Department of Immunology, Nanjing, Jiangsu, China. 5. Nanjing Medical University, Department of Immunology, Nanjing, Jiangsu, China. Electronic address: wanghuijuan@njmu.edu.cn.
Abstract
BACKGROUND: Several studies suggest IL-17 is involved in the pathogenesis of organ fibrosis. The exact role of IL-17 in renal interstitial fibrosis has not been fully elucidated. METHODS: We compared the histopathology of renal fibrosis as well as profibrotic TGF-β signaling in wild-type (WT) and IL-17 knock-out (IL-17-/-) mice using UUO as the disease model. To find out the possible mechanisms involved in the exacerbated renal fibrosis happened to IL-17-/- mice, we analyzed the pattern of ECM synthesis by different fibroblasts cultured with IL-17 and associated signaling mediators. RESULTS: On day3 and day7, IL-17-/- mice developed more severe renal fibrosis compared with WT mice. IL-17 had an inhibitory factor in TGF-β-induced renal fibroblast activation and ECM synthesis, and sequentially in renal interstitial fibrosis, via down-regulation of Smad -independent pathway (p38MAPK and AKT phosphorylations). CONCLUSION: IL-17 acts an inhibitory factor in TGF-β-induced renal fibroblast activation and ECM synthesis, and sequentially in renal interstitial fibrosis, via down-regulation of Smad-independent pathway (p38MAPK and AKT phosphorylations). Clarifying the novel regulatory mechanisms of fibrosis by the cytokine IL-17 may lead to a new therapeutic approach for progressive renal disease and fibrosis.
BACKGROUND: Several studies suggest IL-17 is involved in the pathogenesis of organ fibrosis. The exact role of IL-17 in renal interstitial fibrosis has not been fully elucidated. METHODS: We compared the histopathology of renal fibrosis as well as profibrotic TGF-β signaling in wild-type (WT) and IL-17 knock-out (IL-17-/-) mice using UUO as the disease model. To find out the possible mechanisms involved in the exacerbated renal fibrosis happened to IL-17-/- mice, we analyzed the pattern of ECM synthesis by different fibroblasts cultured with IL-17 and associated signaling mediators. RESULTS: On day3 and day7, IL-17-/- mice developed more severe renal fibrosis compared with WT mice. IL-17 had an inhibitory factor in TGF-β-induced renal fibroblast activation and ECM synthesis, and sequentially in renal interstitial fibrosis, via down-regulation of Smad -independent pathway (p38MAPK and AKT phosphorylations). CONCLUSION:IL-17 acts an inhibitory factor in TGF-β-induced renal fibroblast activation and ECM synthesis, and sequentially in renal interstitial fibrosis, via down-regulation of Smad-independent pathway (p38MAPK and AKT phosphorylations). Clarifying the novel regulatory mechanisms of fibrosis by the cytokine IL-17 may lead to a new therapeutic approach for progressive renal disease and fibrosis.