Journal
AMERICAN JOURNAL OF NEPHROLOGY
Volume 46, Issue 4, Pages 333-342Publisher
KARGER
DOI: 10.1159/000481668
Keywords
Uric acid; Toll-like receptor 4; Epithelial mesenchymal transition; Inflammatory factor
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Funding
- National Key Technology Research and Development (RD) Program [2015BAI12B05]
- National Natural Science Foundation of China [81600569, 81500561, 81500544]
- project for Chongqing basic science and advanced technology research [cst-c2015jcyjBX0028]
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Background: Hyperuricemia is an independent risk factor for causing chronic kidney disease and contributes to kidney fibrosis. After urate crystals get deposited in the kidney, they can cause hyperuricemia nephropathy, leading to glomerular hypertrophy and renal tubular interstitial fibrosis. Recent data showed that uric acid (UA) could induce epithelial mesenchymal transition (EMT) of renal tubular cells, in which NRLP3 inflammatory pathway was involved. However, whether TLR4/NF-kappa B signaling pathway is also involved in EMT of renal tubular cells induced by UA is not clear. Methods: Human renal tubular epithelial cells (HK-2) were directly treated with UA and the phenotypic transition was detected by morphological changes and the molecular markers of EMT. The activation of the TLR4/NF-kappa B signaling pathway induced by UA was measured by Western blot and its involvement was further confirmed by the inhibition of NF-kappa B activation or knockdown of toll like receptor 4 (TLR4) expression. Results: UA induced obvious morphological changes of HK-2 cell, accompanied with altered molecular markers of EMT including fibronectin, alpha-SMA and E-cadherin. In addition, UA significantly upregulated the gene expression of interleukin-1 beta and tumor necrosis factor-a in a time- and dose-dependent manner. Furthermore, UA significantly activated the TLR4/NF-kappa B signaling pathway in HK-2 cells, while the inhibition of the TLR4 expression by siRNA and NF-kappa B activation by PDTC significantly attenuated EMT induced by UA in HK-2 cells. Conclusions: UA can induce EMT in renal tubular epithelial cells by the activation of the TLR4/NF-kappa B signaling pathway, and the targeted intervention of the TLR4/NF-kappa B signaling pathway might effectively inhibit UA-induced renal interstitial fibrosis mediated by EMT. (C) 2017 S. Karger AG, Basel
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