シスプラチンによる腎尿細管性アシドーシス及びアルブミン尿の発症機構

抄録

The mechanisms underlying nephrotoxicity, specifically proximal tubular acidosis and albuminuria, induced by cisplatin (CDDP) were investigated. In the kidney, Na⁺/H⁺ exchanger and vacuolar (V)-H⁺-ATPase are two major H⁺ excretion systems located in the brush-border membrane. In brush-border membrane vesicles isolated from CDDP-treated rats, the activity of V-H⁺-ATPase, but not Na⁺/H⁺ exchanger, decreasedm arkedly. In OK cells, CDDP treatment induced intracellular acidification. Thus, the inhibition of V-H⁺-ATPase would be involved in the proximal tubular acidosis induced by CDDP. V-H⁺-ATPase, as well as chloride channel ClC-5, in the endosomal membrane is important for the endocytic system. In OK cells, endocytosis of albumin was inhibited by CDDP, as well as by inhibitors for V-H⁺-ATPase and ClC-5. In vivo, CDDP administration to rats induced albuminuria, with maximum effect observed at 2-3 days after administration. Such a pattern was comparable with the inhibition of CDDP on V-H⁺-ATPase. Similar pattern was also observed for the urinary excretion of vitamin D binding protein, which is specifically taken up by the proximal tubular cells via megalin-mediated endocytosis. Taken together, the inhibition of V-H⁺-ATPase by CDDP would result in not only proximal tubular acidosis but also albuminuria (proteinuria).