FBXW7 mediates high glucose-induced epithelial to mesenchymal transition via KLF5 in renal tubular cells of diabetic kidney disease.

Tissue & cell [Tissue Cell] 2025 Jun; Vol. 94, pp. 102801. Date of Electronic Publication: 2025 Feb 18.

Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
F-box and WD repeat domain-containing 7 (FBXW7) protein is known as one of the crucial components of the E3 ubiquitin ligase called the Skp1-Cullin1-F-box (SCF) complex, which regulates the degradation of a network of proteins via the ubiquitin-proteasome system. In our study, we investigated the latent impact of FBXW7 on renal tubular cells injury and its molecular mechanism in diabetic kidney disease (DKD). FBXW7 was upregulated in kidneys of diabetic mice and human renal proximal tubular cells exposed to high glucose. Again, the function of experiment found that overexpression of FBXW7 led to epithelial-mesenchymal transition (EMT) of HK2 cells, as indicated by decreased E-cadherin and increased α-smooth muscle actin (α-SMA). Knockdown of FBXW7 ameliorated high glucose-induced EMT of HK2 cells via downregulation of TGF-β1. Then, FBXW7 overexpression downregulated the stability of the KLF5 protein and promoted protein ubiquitination in normal glucose-cultured HK2 cells, which was significantly reversed by the addition of MG132, a specific proteasome inhibitor. Furthermore, overexpression of KLF5 effectively prevented FBXW7 upregulation-induced EMT in HK2 cells. Finally, chemical inhibitors or mTOR kinase dead vector to interfere the activity of mTOR effectively suppressed FBXW7 expression in HK2 cells treated with high glucose. Taken together, these above data suggest that mTOR signaling pathway-regulated FBXW7 mediates high glucose-induced EMT of renal tubular cells by affecting the stability of KLF5.
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English

Publisher: Churchill Livingstone Country of Publication: Scotland NLM ID: 0214745 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1532-3072 (Electronic) Linking ISSN: 00408166 NLM ISO Abbreviation: Tissue Cell Subsets: MEDLINE

Epithelial-Mesenchymal Transition*/drug effects , Epithelial-Mesenchymal Transition*/genetics , F-Box-WD Repeat-Containing Protein 7*/metabolism , F-Box-WD Repeat-Containing Protein 7*/genetics , Glucose*/pharmacology , Glucose*/metabolism , Diabetic Nephropathies*/pathology , Diabetic Nephropathies*/metabolism , Diabetic Nephropathies*/genetics , Kruppel-Like Transcription Factors*/metabolism , Kruppel-Like Transcription Factors*/genetics , Kidney Tubules*/pathology , Kidney Tubules*/metabolism, Animals ; Humans ; Mice ; Cell Line ; Ubiquitination/drug effects ; Male ; Signal Transduction

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