Key role of organic cation transporter 2 for the nephrotoxicity effect of triptolide in rheumatoid arthritis.

Abstract

Tripterygium wilfordii Hook. F. (TwHF), a traditional Chinese Medicine, is effective in treating rheumatoid arthritis (RA), but its severe nephrotoxicity limits its extensive application. The nephrotoxic mechanism of Triptolide (TP), the main pharmacological and toxic component of TwHF, has not been fully revealed. This study was designed to explore the nephrotoxicity of TP in the RA state and the potential molecular mechanism. A rat collagen-induced arthritis (CIA) model was constructed and administered with TP for 28 days in vivo. Results showed that the kidney injury induced by TP was aggravated in the CIA state, the concentration of TP in the renal cortex was higher than that of the medulla after TP administration in the CIA rats, and the expression of organic cation transporter 2 (Oct2) in kidney was up-regulated under CIA condition. Besides, rat kidney slice study demonstrated that TP was transported by Oct2 and this was confirmed by transient silencing and overexpression of OCT2 in HEK-293T cells. Furthermore, cytoinflammatory models on HK-2 and HEK-293T cell lines were constructed by exposure of TNF-α or IL-1β to further explore the TP's renal toxicity. Results suggested that TNF-α exposure aggravated TP's toxicity and up-regulated the protein expression of OCT2 in both cell lines. TNF-α treatment also increased the function of OCT2 and finally OCT2 silencing confirmed OCT2 mediated nephrotoxicity of TP in HEK-293T cells. In summary, the exposure of TNF-α in RA state induced the expression of OCT2, which transported more TP into kidney cortex, subsequently exacerbated the kidney injury.

• Authors: Qingqing Shen, Jingjing Wang, Ziqiao Yuan, Zhenzhou Jiang, Ting Shu, Dengqiu Xu, Jinyong He, Luyong Zhang, Xin Huang
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 77 Pg. 105959 (Dec 2019) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 31644961 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• Cytokines
• Diterpenes
• Epoxy Compounds
• Organic Cation Transporter 2
• Phenanthrenes
• Slc22a2 protein, mouse
• triptolide

Topics

• Animals
• Arthritis, Experimental (metabolism)
• Arthritis, Rheumatoid (drug therapy, metabolism)
• Cell Line
• Cytokines (metabolism)
• Diterpenes (adverse effects, pharmacology)
• Epoxy Compounds (adverse effects, pharmacology)
• Female
• HEK293 Cells
• Humans
• Kidney (drug effects, metabolism)
• Medicine, Chinese Traditional (adverse effects)
• Organic Cation Transporter 2 (metabolism)
• Phenanthrenes (adverse effects, pharmacology)
• Rats
• Rats, Wistar
• Renal Insufficiency (chemically induced, metabolism)
• Tripterygium (adverse effects)
• Up-Regulation (drug effects)