Febuxostat inhibits TGF‑β1‑induced epithelial‑mesenchymal transition via downregulation of USAG‑1 expression in Madin‑Darby canine kidney cells in�vitro

Abstract

Our previous study demonstrated that febuxostat, a xanthine oxidase inhibitor, can alleviate kidney dysfunction and ameliorate renal tubulointerstitial fibrosis in a rat unilateral ureteral obstruction (UUO) model; however, the underlying mechanisms remain unknown. Increasing evidence has revealed that epithelial-mesenchymal transition (EMT) is one of the key mechanisms mediating the progression of renal tubulointerstitial fibrosis in chronic kidney disease (CKD). Uterine sensitization-associated gene-1 (USAG-1), a kidney-specific bone morphogenetic protein antagonist, is involved in the development of numerous types of CKDs. The present study aimed to investigate the role of febuxostat in the process of EMT in Madin-Darby canine kidney (MDCK) cells in vitro . Western blotting, reverse transcription-semiquantitative polymerase chain reaction analysis and immunofluorescence staining were used to evaluate the expression levels of bone morphogenetic protein 7, USAG-1, α-smooth muscle actin (α-SMA) and E-cadherin, respectively. The results demonstrated that the expression of USAG-1 and α-SMA increased, and that of E-cadherin decreased significantly in MDCK cells following treatment with transforming growth factor-β1 (TGF-β1). The application of small interfering RNA-USAG-1 potently inhibited TGF-β1-induced EMT. Subsequently, the effects of febuxostat on TGF-β1-induced EMT was investigated. The results demonstrated that febuxostat downregulated the expression of USAG-1, and reversed TGF-β1-induced EMT in MDCK cells. Furthermore, pretreatment with febuxostat significantly restored the decreased expression levels of phosphorylated Smad1/5/8 induced by TGF-β1 in MDCK cells. The results of the present study suggested that USAG-1 may be involved in the EMT process of MDCK cells induced by TGF-β1, and febuxostat inhibited EMT by activating the Smad1/5/8 signaling pathway via downregulating the expression of USAG-1 in MDCK cells.

The effects of c-Src kinase on EMT signaling pathway in human lens epithelial cells associated with lens diseases

“…This specific process is present in embryonic development, wound healing and tissue repairment and tumor metastasis. In organ fibrosis such as renal fibrosis, pulmonary fibrosis, hepatic fibrosis and ocular fibrosis, EMT is triggered by various biomolecules and signaling pathways, such as transforming growth factor-β (TGF-β) [13], insulin-like growth factor-1 (IGF-1) [14], transcription factor snail [15], and PI3K/Akt/mTOR/NF-κB signaling [16].…”

miR‑155‑5p downregulation inhibits epithelial‑to‑mesenchymal transition by targeting SIRT1 in human nasal epithelial cells

“…EMT is a process by which differentiated epithelial cells undergo phenotypic transformation and acquire the mesenchymal cell phenotype ( 35 ). A previous study reported that ongoing EMT may result in the progression of numerous diseases, such as cancer ( 36 ) and chronic kidney disease ( 37 ), particularly in CRSwNP ( 1 ). Following injury, the expression of junctional proteins, including E-cadherin, are downregulated and the expression of mesenchymal proteins, such as α-SMA, vimentin and fibronectin, are upregulated in epithelial cells, which then undergo EMT and alter morphology ( 38 ).…”

Uterine Sensitization-Associated Gene-1 in the Progression of Kidney Diseases

“…Xia et al found that febuxostat alleviates renal dysfunction and tubulointerstitial fibrosis in rats with UUO by inhibiting USAG-1 expression and activating the BMP7-SMAD1/5/8 pathway [ 31 , 32 ]. In subsequent studies, it was demonstrated that USAG-1 expression is downregulated in vitro in a Madin-Darby canine kidney (MDCK) cell model, which helped reverse TGF- β 1-induced epithelial-mesenchymal transformation (EMT) [ 9 ]. Smad1/5/8 is a key intracellular protein for transducing BMP7 signals, and phosphorylation of Smad1/5/8 is also the central downstream event in the BMP signal transduction pathway [ 5 , 9 , 33 ].…”