Cisplatin-induced inhibition of receptor-mediated endocytosis of protein in the kidney.
BACKGROUND
Administration of cisplatin, cis-diamminedichloroplatinum (II) (CDDP), causes a severe impairment of renal function, including increases in urinary excretion of proteins. We recently found that CDDP inhibits vacuolar H+-ATPase, which plays an important role in receptor-mediated endocytosis in the renal proximal tubules. Therefore, CDDP-induced proteinuria may be due to an inhibition of the receptor-mediated endocytosis in the renal proximal tubules following a decrease in vacuolar H+-ATPase activity by the drug.


METHODS
Effects of CDDP on receptor-mediated endocytosis of albumin in opossum kidney (OK) epithelial cells, and on urinary excretion of albumin and vitamin D binding protein, which are reabsorbed in the renal proximal tubules by endocytosis, in rats were examined.


RESULTS
CDDP inhibited uptake of fluorescein-isothiocyanate (FITC)-albumin, a receptor-mediated endocytosis marker, by OK cells in a time- and concentration-dependent fashion. In contrast, CDDP treatment did not affect the uptake of FITC-inulin, a fluid-phase endocytosis marker. CDDP caused a decrease in the affinity and in the maximal velocity of FITC-albumin uptake. The adenosine 5'-triphosphate (ATP) content in OK cells was not changed by CDDP at concentrations that inhibited FITC-albumin uptake. The endosomal pH in OK cells was increased by CDDP treatment. Administration of CDDP to rats increased the urinary excretion of albumin and vitamin D binding protein.


CONCLUSIONS
These results suggest that CDDP decreases the receptor-mediated endocytosis of protein following the inhibition of vacuolar H+-ATPase in the renal proximal tubules, and the inhibition of receptor-mediated endocytosis would be the mechanisms underlying the proteinuria induced by CDDP.
Takano
Mikihisa
M
Institute of Pharmaceutical Sciences, Faculty of Medicine, Hiroshima University, Hiroshima, Japan. takanom@hiroshima-u.ac.jp
Nakanishi
Naoki
N
Kitahara
Yasumi
Y
Sasaki
Yuki
Y
Murakami
Teruo
T
Nagai
Junya
J
D000255:Adenosine Triphosphate / Q000378:metabolism; D000418:Albumins / Q000493:pharmacokinetics; D000419:Albuminuria / Q000139:chemically induced / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016190:Carboplatin / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018118:Chloride Channels / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D004705:Endocytosis / Q000187:drug effects*; D016650:Fluorescein-5-isothiocyanate / Q000493:pharmacokinetics; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D007672:Kidney Cortex / Q000166:cytology / Q000378:metabolism*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000378:metabolism; D008297:Male; D009893:Opossums; D051381:Rats; D017208:Rats, Wistar; D014807:Vitamin D / Q000378:metabolism; D014809:Vitamin D-Binding Protein / Q000652:urine
D000418:Albumins; D000970:Antineoplastic Agents; C097503:CLC-5 chloride channel; D018118:Chloride Channels; D005456:Fluorescent Dyes; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D014809:Vitamin D-Binding Protein; D014807:Vitamin D; D000255:Adenosine Triphosphate; D016190:Carboplatin; D016650:Fluorescein-5-isothiocyanate; D002945:Cisplatin