期刊
FRONTIERS IN PHYSIOLOGY
卷 12, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fphys.2021.709506
关键词
diabetic kidney disease; epithelial-mesenchymal transition; fibrosis; inflammation; tripartite motif family proteins
类别
资金
- Zhejiang Provincial Medical and Health Technology Project [2021427856]
DKD is a leading cause of end-stage renal disease worldwide, with inflammation and fibrosis playing important roles in its pathogenesis. TRIM18 has been identified as a key player in DKD, with knockdown of TRIM18 inhibiting HG-induced EMT, inflammation, and fibrosis in kidney cells. The TRIM18/PTP1B/STAT3 signaling pathway could be a promising target for potential therapeutics in DKD treatment.
Diabetic kidney disease (DKD) has become a key cause of end-stage renal disease worldwide. Inflammation and fibrosis have been shown to play important roles in the pathogenesis of DKD. MID1, also known as TRIM18, is an E3 ubiquitin ligase of the tripartite motif (TRIM) subfamily of RING-containing proteins and increased in renal tubule in patients with DKD. However, the function and molecular mechanism of TRIM18 in DKD remain unexplored. Herein we report that TRIM18 expression levels were increased in patients with DKD. An animal study confirms that TRIM18 is involved in kidney injury and fibrosis in diabetic mice. TRIM18 knockdown inhibits high glucose (HG)-induced epithelial-mesenchymal transition (EMT), inflammation, and fibrosis of HK-2 cells. This is accompanied by decreased levels of tumor necrosis factor alpha, interleukin-6, hydroxyproline (Hyp), connective tissue growth factor, and alpha-smooth muscle actin. Additionally, TRIM18 knockdown inhibits HG-induced increase in the phosphorylated-/total signal transducer and activator of transcription (STAT3). Treatment with niclosamide (STAT3 inhibitor) or protein tyrosine phosphatase-1B (PTP1B) overexpression blocked the TRIM18 induced EMT, inflammation and fibrosis. Co-immunoprecipitation and Western blot assays showed that TRIM18 promoted the ubiquitination of PTP1B. These findings highlight the importance of the TRIM18/PTP1B/STAT3 signaling pathway in DKD and can help in the development of new therapeutics for DKD treatment.
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