TY - JOUR
T1 - Discovery of PRDM16-Mediated TRPA1 Induction as the Mechanism for Low Tubulo-Interstitial Fibrosis in Diabetic Kidney Disease
AU - Xu, Fang
AU - Jiang, Hongwei
AU - Li, Xiaozhou
AU - Pan, Jian
AU - Li, Huiling
AU - Wang, Luxiang
AU - Zhang, Pan
AU - Chen, Junxiang
AU - Qiu, Shuangfa
AU - Xie, Yuxin
AU - Li, Yijian
AU - Zhang, Dongshan
AU - Dong, Zheng
N1 - Publisher Copyright:
© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.
PY - 2024/2/16
Y1 - 2024/2/16
N2 - The pathogenesis of Diabetic kidney disease(DKD) involves pathological changes in both tubulo-interstitium and the glomerulus. Surprisingly, tubulo-interstitial fibrosis (TIF), does not develop significantly until the late stage of DKD. Here, it is demonstrated that PR domain-containing 16 (PRDM16) is a key to the low level of TIF in DKD. In the experiments, PRDM16 is upregulated in high glucose-treated renal tubular cells, DKD mouse kidneys, and renal biopsy of human DKD patients via activation of NF-κB signal pathway. High glucose-induced expression of fibrotic proteins in renal tubular cells is suppressed by PRDM16. Mechanistically, PRDM16 bound to the promotor region of Transient receptor potential ankyrin 1 (TRPA1) to transactivate its expression and then suppressed MAPK (P38, ERK1/2) activation and downstream expression of TGF-β1. Knockout of PRDM16 from kidney proximal tubules in mice blocked TRPA1 expression and enhanced MAPK activation, TGF-β1 production, TIF development, and DKD progression, whereas knock-in of PRDM16 has opposite effects. In addition, overexpression of PRDM16 or its induction by formononetin ameliorated renal dysfunction and fibrosis in db/db diabetic mice. Finally, the above finding are detected in renal biopsies of DKD patients. Together, these results unveil PRDM16/TRPA1 as the mechanism responsible for the low level of TIF in the early stage of DKD by suppressing and TGF-β1 expression.
AB - The pathogenesis of Diabetic kidney disease(DKD) involves pathological changes in both tubulo-interstitium and the glomerulus. Surprisingly, tubulo-interstitial fibrosis (TIF), does not develop significantly until the late stage of DKD. Here, it is demonstrated that PR domain-containing 16 (PRDM16) is a key to the low level of TIF in DKD. In the experiments, PRDM16 is upregulated in high glucose-treated renal tubular cells, DKD mouse kidneys, and renal biopsy of human DKD patients via activation of NF-κB signal pathway. High glucose-induced expression of fibrotic proteins in renal tubular cells is suppressed by PRDM16. Mechanistically, PRDM16 bound to the promotor region of Transient receptor potential ankyrin 1 (TRPA1) to transactivate its expression and then suppressed MAPK (P38, ERK1/2) activation and downstream expression of TGF-β1. Knockout of PRDM16 from kidney proximal tubules in mice blocked TRPA1 expression and enhanced MAPK activation, TGF-β1 production, TIF development, and DKD progression, whereas knock-in of PRDM16 has opposite effects. In addition, overexpression of PRDM16 or its induction by formononetin ameliorated renal dysfunction and fibrosis in db/db diabetic mice. Finally, the above finding are detected in renal biopsies of DKD patients. Together, these results unveil PRDM16/TRPA1 as the mechanism responsible for the low level of TIF in the early stage of DKD by suppressing and TGF-β1 expression.
KW - MAPK
KW - PRDM16
KW - TGF-β1
KW - TRPA1
KW - diabetic kidney disease
KW - tubulo-interstitial fibrosis
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U2 - 10.1002/advs.202306704
DO - 10.1002/advs.202306704
M3 - Article
C2 - 38072665
AN - SCOPUS:85179308327
SN - 2198-3844
VL - 11
JO - Advanced Science
JF - Advanced Science
IS - 7
M1 - 2306704
ER -