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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Paclitaxel Ameliorates Lipopolysaccharide-Induced Kidney Injury by Binding Myeloid Differentiation Protein-2 to Block Toll-Like Receptor 4–Mediated Nuclear Factor-κB Activation and Cytokine Production

Dongshan Zhang, Yijian Li, Yu Liu, Xudong Xiang and Zheng Dong
Journal of Pharmacology and Experimental Therapeutics April 2013, 345 (1) 69-75; DOI: https://doi.org/10.1124/jpet.112.202481
Dongshan Zhang
Departments of Emergency Medicine (D.Z., Yi.L., X.X.) and Nephrology (Yu.L., Z.D.), Second Xiangya Hospital, Central South University, Changsha, Hunan, China; and Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia (D.Z., Yu.L., Z.D.)
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Yijian Li
Departments of Emergency Medicine (D.Z., Yi.L., X.X.) and Nephrology (Yu.L., Z.D.), Second Xiangya Hospital, Central South University, Changsha, Hunan, China; and Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia (D.Z., Yu.L., Z.D.)
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Yu Liu
Departments of Emergency Medicine (D.Z., Yi.L., X.X.) and Nephrology (Yu.L., Z.D.), Second Xiangya Hospital, Central South University, Changsha, Hunan, China; and Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia (D.Z., Yu.L., Z.D.)
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Xudong Xiang
Departments of Emergency Medicine (D.Z., Yi.L., X.X.) and Nephrology (Yu.L., Z.D.), Second Xiangya Hospital, Central South University, Changsha, Hunan, China; and Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia (D.Z., Yu.L., Z.D.)
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Zheng Dong
Departments of Emergency Medicine (D.Z., Yi.L., X.X.) and Nephrology (Yu.L., Z.D.), Second Xiangya Hospital, Central South University, Changsha, Hunan, China; and Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia (D.Z., Yu.L., Z.D.)
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Abstract

Recent studies suggest that paclitaxel, an anticancer agent, may modulate the injury and inflammatory responses in normal tissues. However, the underlying mechanism is not fully understood. Here we have examined the effect of paclitaxel on lipopolysaccharide (LPS)–induced acute kidney injury (AKI) in mice and further studied the mechanism. At relatively low doses, paclitaxel protected against LPS-induced AKI and improved animal survival. The beneficial effects of paclitaxel were accompanied by the downregulation of tumor necrosis factor-α, interleukin-1, and interleukin-6 production. In cultured renal tubular HK-2 cells, paclitaxel decreased the DNA-binding activity of nuclear factor-κB (NF-κB) during LPS treatment, inhibited the degradation of the inhibitor of κB-α, and blocked the expression and activation of NF-κB p65. At the upstream level, paclitaxel reduced LPS-induced association of myeloid differentiation protein-2 (MD-2) with Toll-like receptor 4 (TLR4). In an in vitro assay, paclitaxel was shown to directly bind recombinant MD-2. The inhibitory effect of paclitaxel on NF-κB activation and cytokine expression disappeared in MD-2 knockdown cells, indicating that paclitaxel acts through MD-2. Collectively, these results suggest that paclitaxel may bind MD-2 to block MD-2/TLR4 association during LPS treatment, resulting in the suppression of NF-κB activation and inhibition of proinflammatory cytokine production.

Footnotes

    • Received December 6, 2012.
    • Accepted January 11, 2013.
  • D.Z. and Yi.L. contributed equally to this work.

  • This research was supported in part by the National Natural Science Foundation of China [Grant 81100507/H0509]; the National Basic Research Program of China 973 Program No. 2012CB517600 [Grant 2012CB517601]; the Central South University Free Exploration Research Program [Grant 2011QNZT172]; the National Institutes of Health [Grants 2R01-DK58831 and 1R01-DK87843]; and the US Department of Veterans Affairs [Merit Review].

  • dx.doi.org/10.1124/jpet.112.202481.

  • U.S. Government work not protected by U.S. copyright
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Journal of Pharmacology and Experimental Therapeutics: 345 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 345, Issue 1
1 Apr 2013
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Kidney Protection by Paclitaxel

Dongshan Zhang, Yijian Li, Yu Liu, Xudong Xiang and Zheng Dong
Journal of Pharmacology and Experimental Therapeutics April 1, 2013, 345 (1) 69-75; DOI: https://doi.org/10.1124/jpet.112.202481

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Kidney Protection by Paclitaxel

Dongshan Zhang, Yijian Li, Yu Liu, Xudong Xiang and Zheng Dong
Journal of Pharmacology and Experimental Therapeutics April 1, 2013, 345 (1) 69-75; DOI: https://doi.org/10.1124/jpet.112.202481
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