Abstract | BACKGROUND AND PURPOSE: EXPERIMENTAL APPROACH: The effect of cilastatin was evaluated in diclofenac-induced acute kidney injury in mice. Human OAT1/3-transfected HEK293 cells and renal primary proximal tubule cells (RPTCs) were used to investigate OAT1/3-mediated transport and the cytotoxicity of diclofenac. KEY RESULTS:
Cilastatin treatment decreased the pathological changes, renal dysfunction and elevated renal levels of oxidation products, cytokine production and apoptosis induced by diclofenac in mice. Moreover, cilastatin increased the plasma concentration and decreased the renal distribution of diclofenac and its glucuronide metabolite, diclofenac acyl glucuronide (DLF-AG). Similarly, cilastatin inhibited cytotoxicity and mitochondrial damage in RPTCs but did not change the intracellular accumulation of diclofenac. DLF-AG but not diclofenac exhibited OAT-dependent cytotoxicity and was identified as an OAT1/3 substrate. Cilastatin inhibited the intracellular accumulation and decreased the cytotoxicity of DLF-AG in RPTCs. CONCLUSION AND IMPLICATIONS:
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Authors | Xiaokui Huo, Qiang Meng, Changyuan Wang, Jingjing Wu, Chong Wang, Yanna Zhu, Xiaodong Ma, Huijun Sun, Kexin Liu |
Journal | British journal of pharmacology
(Br J Pharmacol)
Vol. 177
Issue 9
Pg. 1933-1948
(05 2020)
ISSN: 1476-5381 [Electronic] England |
PMID | 32000294
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2020 The British Pharmacological Society. |
Chemical References |
- 1-O-(2-((2',6'-dichlorophenyl)amino)phenylacetyl)glucopyranuronic acid
- Glucuronides
- Organic Anion Transporters
- Organic Anion Transporters, Sodium-Independent
- Cilastatin
- Diclofenac
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Topics |
- Animals
- Cilastatin
- Diclofenac
(analogs & derivatives, toxicity)
- Glucuronides
- HEK293 Cells
- Humans
- Kidney
- Mice
- Organic Anion Transporters
- Organic Anion Transporters, Sodium-Independent
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