Effect of cisplatin on H⁺ transport by H⁺-ATPase and Na⁺/H⁺ exchanger in rat renal brush-border membrane

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• 作者：Shiraishi ; Yoshiki ; Nagai ; Junya ; Murakami ; Teruo ; Takano ; Mikihisa
• 关键词：Cis-diamminedichloroplatinum (II) ; Vacuolar H⁺-ATPase ; Na⁺/H⁺ exchanger ; Renal brush-border membrane ; H⁺ secretion
• 刊名：Life Sciences
• 出版年：2000
• 期刊代码：62_00243205
• 类别：imm
• 出版时间：July 21, 2000
• 卷：67
• 期：9
• 页码：1047-1058
• 文件大小：230 K

摘要

The effect of the potent anticancer drug cisplatin, cis-diamminedichloroplatinum (II) (CDDP), on H⁺-ATPase and Na⁺/H⁺ exchanger in rat renal brush-border membrane was examined. To measure H⁺ transport by vacuolar H⁺-ATPase in renal brush-border membrane vesicles, we employed a detergent-dilution procedure, which can reorientate the catalytic domain of H⁺-ATPase from an inward-facing configuration to outward-facing one. ATP-driven H⁺ pump activity decreased markedly in brush-border membrane prepared from rats two days after CDDP administration (5 mg/kg, i.p.). In addition, N-ethylmaleimide and bafilomycin A₁ (inhibitors of vacuolar H⁺-ATPase)-sensitive ATPase activity also decreased in these rats. The decrease in ATP-driven H⁺ pump activity was observed even at day 7 after the administration of CDDP. Suppression of ATP-driven H⁺ pump activity was also observed when brush-border membrane vesicles prepared from normal rats were pretreated with CDDP in vitro. In contrast with H⁺-ATPase, the activity of Na⁺/H⁺ exchanger, which was determined by measuring acridine orange fluorescence quenching, was not affected by the administration of CDDP. These results provide new insights into CDDP-induced renal tubular dysfunctions, especially such as proximal tubular acidosis and proteinuria.