TY - JOUR
T1 - IL-17 receptor signaling negatively regulates the development of tubulointerstitial fibrosis in the kidney
AU - Ramani, Kritika
AU - Tan, Roderick J.
AU - Zhou, Dong
AU - Coleman, Bianca M.
AU - Jawale, Chetan V.
AU - Liu, Youhua
AU - Biswas, Partha S.
N1 - Publisher Copyright: © 2018 Kritika Ramani et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
PY - 2018
Y1 - 2018
N2 - Chronic inflammation has an important role in the development and progression of most fibrotic diseases, for which no effective treatments exist. Tubulointerstitial fibrosis (TF) is characterized by irreversible deposition of fibrous tissue in chronic kidney diseases. Prolonged injurious stimuli and chronic inflammation regulate downstream events that lead to TF. In recent years, interleukin-17 (IL-17) has been strongly linked to organ fibrosis. However, the role of IL-17 receptor signaling in TF is an active area of debate. Using the unilateral ureteral obstruction (UUO) mouse model of TF, we show that IL-17 receptor A-deficient mice (Il17ra − / − ) exhibit increased TF in the obstructed kidney. Consequently, overexpression of IL-17 restored protection in mice with UUO. Reduced renal expression of matrix-degrading enzymes results in failure to degrade ECM proteins, thus contributing to the exaggerated TF phenotype in Il17ra − / − mice. We demonstrate that the antifibrotic kallikrein-kinin system (KKS) is activated in the obstructed kidney in an IL-17-dependent manner. Accordingly, Il17ra − / − mice receiving bradykinin, the major end-product of KKS activation, prevents TF development by upregulating the expression of matrix-degrading enzymes. Finally, we show that treatment with specific agonists for bradykinin receptor 1 or 2 confers renal protection against TF. Overall, our results highlight an intriguing link between IL-17 and activation of KKS in protection against TF, the common final outcome of chronic kidney conditions leading to devastating end-stage renal diseases.
AB - Chronic inflammation has an important role in the development and progression of most fibrotic diseases, for which no effective treatments exist. Tubulointerstitial fibrosis (TF) is characterized by irreversible deposition of fibrous tissue in chronic kidney diseases. Prolonged injurious stimuli and chronic inflammation regulate downstream events that lead to TF. In recent years, interleukin-17 (IL-17) has been strongly linked to organ fibrosis. However, the role of IL-17 receptor signaling in TF is an active area of debate. Using the unilateral ureteral obstruction (UUO) mouse model of TF, we show that IL-17 receptor A-deficient mice (Il17ra − / − ) exhibit increased TF in the obstructed kidney. Consequently, overexpression of IL-17 restored protection in mice with UUO. Reduced renal expression of matrix-degrading enzymes results in failure to degrade ECM proteins, thus contributing to the exaggerated TF phenotype in Il17ra − / − mice. We demonstrate that the antifibrotic kallikrein-kinin system (KKS) is activated in the obstructed kidney in an IL-17-dependent manner. Accordingly, Il17ra − / − mice receiving bradykinin, the major end-product of KKS activation, prevents TF development by upregulating the expression of matrix-degrading enzymes. Finally, we show that treatment with specific agonists for bradykinin receptor 1 or 2 confers renal protection against TF. Overall, our results highlight an intriguing link between IL-17 and activation of KKS in protection against TF, the common final outcome of chronic kidney conditions leading to devastating end-stage renal diseases.
UR - https://www.scopus.com/pages/publications/85056254292
U2 - 10.1155/2018/5103672
DO - 10.1155/2018/5103672
M3 - Article
C2 - 30405320
SN - 0962-9351
VL - 2018
JO - Mediators of Inflammation
JF - Mediators of Inflammation
M1 - 5103672
ER -