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Heat Shock Protein 72 Protects Kidney Proximal Tubule Cells From Injury Induced by Triptolide by Means of Activation of the MEK/ERK Pathway

From the Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi’an, Shaanxi, China; State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shaanxi Provine, China; Department of Gastroenterology, Bethune International Peace Hospital, Shijiazhuang, Hebei Province, P.R. China; Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi’an, Shaanxi, China; Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi’an, Shaanxi, China; Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi’an, Shaanxi, China; and State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shaanxi, China.

Correspondence: Please address correspondence to Zhipeng Wang, Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi’an, Shaanxi, 710032, China; e-mail:wangzhipeng7763{at}yahoo.com.cn.

Triptolide, which has been used to treat inflammatory diseases, has also been reported to inhibit proliferation of cancer cells. However, it can cause severe nephrotoxicity, limiting its clinical use. Here, nephrotoxicity of triptolide was observed in vivo and in vitro. Heat shock protein 72 (HSP72) was upregulated during kidney injury in rats. HSP72 partially protected human kidney proximal tubule cell lines HK-2 and HKC from triptolide-induced injury. Phospho-Raf, phospho-MEK and phospho-ERK were elevated in HK-2 cells that overexpressed HSP72 after either heat shock or triptolide treatment, and downregulated when HSP72 was repressed by siRNA. The participation of the MEK/ERK1/2 pathway was confirmed by exposure of the cells to the MEK inhibitor U0126. Collectively, our results suggested that HSP72 plays a protective role by means of the MEK/ERK pathway, against triptolide-induced kidney injury.

Key Words: ERK1/2 • heat shock protein 72 • MEK • nephrotoxicity • triptolide

International Journal of Toxicology, Vol. 28, No. 3, 177-189 (2009)
DOI: 10.1177/1091581809337418


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