Renal-targeting triptolide-glucosamine conjugate exhibits lower toxicity and superior efficacy in attenuation of ischemia/reperfusion renal injury in rats

Aim： We previously reported a novel triptolide （TP）-glucosamine conjugate （TPG） that specifically accumulated in kidneys and protected renal function from acute ischemia/reperfusion （I/R） injury in rats. In this study we further examined the molecular mechanisms underlying the renoprotective action...

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Bibliographic Details
Published in:Acta pharmacologica Sinica 2016-11, Vol.37 (11), p.1467-1480
Main Authors: Fu, Yu, Lin, Qing, Gong, Tao, Sun, Xun, Zhang, Zhi-Rong
Format: Article
Language:English
Subjects:
Acute Kidney Injury - drug therapy
Acute Kidney Injury - metabolism
Acute Kidney Injury - pathology
Animals
Apoptosis
Cell Adhesion
Cell Adhesion Molecules - metabolism
Cell Line
Cell Movement
Diterpenes - therapeutic use
Diterpenes - toxicity
Glucosamine - therapeutic use
Glucosamine - toxicity
Humans
Ischemia - drug therapy
Ischemia - metabolism
Ischemia - pathology
Kidney - blood supply
Kidney - drug effects
Kidney - metabolism
Kidney - pathology
Kidney Tubules - metabolism
Kidney Tubules - pathology
Leukocytes - physiology
Lipid Peroxidation
Male
Molecular Targeted Therapy
Necrosis
Original
Oxidative Stress
Rats, Sprague-Dawley
Reperfusion Injury - drug therapy
Reperfusion Injury - metabolism
Reperfusion Injury - pathology
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Summary:Aim： We previously reported a novel triptolide （TP）-glucosamine conjugate （TPG） that specifically accumulated in kidneys and protected renal function from acute ischemia/reperfusion （I/R） injury in rats. In this study we further examined the molecular mechanisms underlying the renoprotective action of TPG. Methods： The renal-targeting of TPG was investigated in a human proximal renal tubular epithelial cell line （HK-2） by measuring cell uptake of TP or TPG. The effects of TP or TPG on cell cycle distribution and apoptosis rate of HK-2 cells were assessed, and the activities of caspase-3 and caspase-9 were also measured. SD rats were subjected to bilateral renal ischemia by temporarily clamping both renal pedicles. The rats were administered TP （4.17 μmol·kg^-1·d^-1, iv） or TPG （4.17 μmol·kg^-1·d^-1, iv） for 3 d before the renal surgery. The kidneys were harvested after 24 h of recovery from the surgery. The levels of oxidative stress, proinflammatory cytokines, chemotactic cytokines and intracellular adhesion molecules in kidneys were examined. Results： The uptake of TPG in HK-2 cells was 2-3 times higher than that of TP at the concentrations tested. Furthermore, TPG targeting the proximal tubules was mediated through interactions with megalin receptors. TP （40-160 nmol/L） concentration-dependently increased GJM arrest, apoptosis and caspase-3/caspase-9 activity in HK-2 cells, whereas the same concentrations of TPG did not show those features when compared with the control group. In I/R-treated rats, TPG administration caused more robust down-regulation of proinflammatory cytokines （TNF-α, IL-6, IL-1, TGF-β） and chemotactic cytokines （MCP-1） in the kidneys compared with TP administration, suggesting the inhibition of the proliferation and accumulation of lymphocytes. And TPG administration also caused more prominent inhibition on the levels of oxidative stress and intracellular adhesion molecules in the kidneys, compared with TP administration. Conclusion： The renal-targeting TPG is more effective and less toxic than TP, in amelioration of I/R-induced rat renal injury, which may provide a new avenue for the treatment of acute kidney injury.
ISSN:1671-4083
1745-7254
DOI:10.1038/aps.2016.44