Downregulated expression of intestinal P-glycoprotein in rats with cisplatin-induced acute kidney injury causes amplification of its transport capacity to maintain 'gatekeeper' function
| Autor: | Masaru Terasaki, Yuichi Ichimura, Masako Oda, Hiroshi Saitoh, Fuyo Takeda, Hiroyuki Kojima |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Abcg2 Down-Regulation Gene Expression Ileum Antineoplastic Agents Pharmacology urologic and male genital diseases Toxicology Rhodamine 123 Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Organ Culture Techniques Intestine Small medicine ATP Binding Cassette Transporter Subfamily G Member 2 Animals ATP Binding Cassette Transporter Subfamily B Member 1 P-glycoprotein Cisplatin Kidney biology Acute kidney injury Acute Kidney Injury medicine.disease female genital diseases and pregnancy complications Rats 030104 developmental biology medicine.anatomical_structure chemistry 030220 oncology & carcinogenesis biology.protein Verapamil medicine.drug |
| Zdroj: | Toxicology and applied pharmacology. 423 |
| ISSN: | 1096-0333 |
| Popis: | The expression of transporters on the apical and basal membranes of renal proximal tubular cells are down- or upregulated to various extents under cisplatin (CDDP)-induced acute kidney injury (AKI). However, little is known about the changes in transporters in tissues other than the kidney under CDDP-induced AKI. This study aimed to investigate the modulation of the expression/function of intestinal efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), in CDDP-induced AKI rats. On day 3 after the intraperitoneal administration of CDDP (5 mg/kg) to rats, the expression levels of P-gp and Bcrp were compared with those of normal rats. Further, the absorption of three P-gp substrates (6α-methylprednisolone, rhodamine 123, and gatifloxacin) was evaluated in both groups using conventional loop techniques. In the CDDP-induced AKI rats, P-gp expression in the ileum was markedly decreased to approximately 38% of that in the normal rats. However, no significant changes in Bcrp expression were observed in the AKI rats. In contrast with the reduction in P-gp expression in the AKI rats, the absorption of the three P-gp substrates remained almost the same or decreased in the AKI group. The addition of verapamil (a potent P-gp inhibitor) increased the absorption of the three P-gp substrates to the values obtained from the normal rats. In conclusion, our results suggested that P-gp expression is downregulated in rats with CDDP-induced AKI but that P-gp maintains its potency as a “gatekeeper” against the absorption of xenobiotics by amplifying its individual transport capacity under these conditions. |
| Databáze: | OpenAIRE |
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