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Renal interstitial fibrosis induced by high-dose mesoporous silica nanoparticles via the NF-?B signaling pathway.

ABSTRACT: Previous studies have indicated that the nephrotoxicity induced by mesoporous silica nanoparticles (MSNs) is closely related to inflammation. Nuclear factor kappa B (NF-?B), a common rapid transcription factor associated with inflammation, plays an important role in the process of many kidney diseases. Acute toxicity assessment with a high-dose exposure is critical for the development of nanoparticle, as a part of standardized procedures for the evaluation of their toxicity. The present study was undertaken to observe the acute toxicity, predict the potential target organs of MSNs injury, and test the hypothesis that the NF-?B pathway plays a role in mediating the acute kidney injury and renal interstitial fibrosis in mice induced by MSNs. Balb/c mice were intraperitoneally injected with MSNs at concentrations of 150, 300, or 600 mg/kg. All of the animals were euthanized 2 and 12 days after exposure, and the blood and kidney tissues were collected for further studies. In vitro, the cytotoxicity, fibrosis markers, and NF-?B pathway were measured in a normal rat kidney cell line (NRK-52E). Acute kidney injury was induced by MSNs in mice after 2 days, some renal tubules regenerated and renal interstitial fibrosis was also observed. The expression of fibrosis markers and the nuclear translocation of NF-?B p65 in the kidney homogenates increased after exposure to MSNs. The in vitro study showed that MSNs cause cytotoxicity in NRK-52E cells and increased the expression of fibrosis markers. In addition, the NF-?B pathway could be induced, and inhibition of the NF-?B pathway could alleviate the fibrosis caused by MSNs. We conclude that inflammation is a major effector of the acute kidney toxicity induced by MSNs and results in renal interstitial fibrosis, which is mediated by the NF-?B signaling pathway.

SUBMITTER: Chen X

PROVIDER: S-EPMC4275059 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Renal interstitial fibrosis induced by high-dose mesoporous silica nanoparticles via the NF-κB signaling pathway.

Chen Xi X Zhouhua Wang W Jie Zhou Z Xinlu Fu F Jinqiang Liang L Yuwen Qiu Q Zhiying Huang H

International journal of nanomedicine 20141218

Previous studies have indicated that the nephrotoxicity induced by mesoporous silica nanoparticles (MSNs) is closely related to inflammation. Nuclear factor kappa B (NF-κB), a common rapid transcription factor associated with inflammation, plays an important role in the process of many kidney diseases. Acute toxicity assessment with a high-dose exposure is critical for the development of nanoparticle, as a part of standardized procedures for the evaluation of their toxicity. The present study wa ...[more]

PMID: 25565800

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Project description:Salidroside (Sal) is an active ingredient that is isolated from Rhodiola rosea, which has been reported to have anti-inflammatory activities and a renal protective effect. However, the role of Sal on renal fibrosis has not yet been elucidated. Here, the purpose of the current study is to test the protective effects of Sal against renal interstitial fibrosis (RIF), and to explore the underlying mechanisms using both in vivo and in vitro models. In this study, we establish the unilateral ureteric obstruction (UUO) or folic acid (FA)-induced mice renal interstitial fibrosis in vivo and the transforming growth factor (TGF)-β1-stimulated human proximal tubular epithelial cell (HK-2) model in vitro. The levels of kidney functional parameters and inflammatory cytokines in serum are examined. The degree of renal damage and fibrosis is determined by histological assessment. Immunohistochemistry and western blotting are used to determine the mechanisms of Sal against RIF. Our results show that treatment with Sal can ameliorate tubular injury and deposition of the extracellular matrix (ECM) components (including collagen Ш and collagen I). Furthermore, Sal administration significantly suppresses epithelial-mesenchymal transition (EMT), as evidenced by a decreased expression of α-SMA, vimentin, TGF-β1, snail, slug, and a largely restored expression of E-cadherin. Additionally, Sal also reduces the levels of serum biochemical markers (serum creatinine, Scr; blood urea nitrogen, BUN; and uric acid, UA) and decreases the release of inflammatory cytokines (IL-1β, IL-6, TNF-α). Further study revealed that the effect of Sal on renal interstitial fibrosis is associated with the lower expression of TLR4, p-IκBα, p-NF-κB and mitogen-activated protein kinases (MAPK), both in vivo and in vitro. In conclusion, Sal treatment improves kidney function, ameliorates the deposition of the ECM components and relieves the protein levels of EMT markers in mouse kidneys and HK-2 cells. Furthermore, Sal treatment significantly decreases the release of inflammatory cytokines and inhibits the TLR4/NF-κB and MAPK signaling pathways. Collectively, these results suggest that the administration of Sal could be a novel therapeutic strategy in treating renal fibrosis.

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Renal interstitial fibrosis induced by high-dose mesoporous silica nanoparticles via the NF-?B signaling pathway.

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Renal interstitial fibrosis induced by high-dose mesoporous silica nanoparticles via the NF-κB signaling pathway.

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