Renal transporter OAT1 and PPAR-α pathway co-contribute to icaritin-induced nephrotoxicity.
Phytother Res
; 37(2): 549-562, 2023 Feb.
Article
em En
| MEDLINE
| ID: mdl-36331006
ABSTRACT
This study aimed to investigate the potential nephrotoxicity of icaritin and the underlying mechanism by in vitro-in vivo experiment technology combined with proteomics technology. First, icaritin showed a significant cytotoxic effect on HK-2 cells, which was accompanied by increased LDH and TNF-α in the supernatant, decreased protein expressions of Bcl-2 and increased Bax and enhanced apoptosis of HK-2 cells as measured by TUNEL staining. Moreover, icaritin induced obvious tubular damage and up-regulation of BUN and CRE levels in plasma in mice. Second, intracellular uptake of icaritin was considerably higher in hOAT1-HEK293 cells than in mock-HEK293 cells, suggesting that icaritin might accumulate in renal cells via OAT1 uptake. Importantly, icaritin caused significant changes in the PPAR signaling pathway in HK2 cells through proteomic analysis. Then, in vitro and in vivo results verified that icaritin significantly downregulated the protein expression of PPAR-α as well as downregulated APOB, ACSL3, ACSL4, and upregulated 5/12/15-HETE, implying that a lipid metabolism disorder was involved in the icaritin-induced nephrotoxicity. Finally, icaritin was found to increase the accumulation of iron and LPO levels while reducing the activity of GPX4, suggesting that ferroptosis was involved in the nephrotoxicity induced by icaritin.
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Base de dados:
MEDLINE
Assunto principal:
Proteômica
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Receptores Ativados por Proliferador de Peroxissomo
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article