Cisplatin-induced inhibition of receptor-mediated endocytosis of protein in the kidney

Kidney Int. 2002 Nov;62(5):1707-17. doi: 10.1046/j.1523-1755.2002.00623.x.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Albumins / pharmacokinetics
  • Albuminuria / chemically induced
  • Albuminuria / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Carboplatin / pharmacology
  • Cell Survival / drug effects
  • Cells, Cultured
  • Chloride Channels / metabolism
  • Cisplatin / pharmacology*
  • Endocytosis / drug effects*
  • Fluorescein-5-isothiocyanate / pharmacokinetics
  • Fluorescent Dyes / pharmacokinetics
  • Kidney Cortex / cytology
  • Kidney Cortex / metabolism*
  • Low Density Lipoprotein Receptor-Related Protein-2 / metabolism
  • Male
  • Opossums
  • Rats
  • Rats, Wistar
  • Vitamin D / metabolism
  • Vitamin D-Binding Protein / urine

Substances

  • Albumins
  • Antineoplastic Agents
  • CLC-5 chloride channel
  • Chloride Channels
  • Fluorescent Dyes
  • Low Density Lipoprotein Receptor-Related Protein-2
  • Vitamin D-Binding Protein
  • Vitamin D
  • Adenosine Triphosphate
  • Carboplatin
  • Fluorescein-5-isothiocyanate
  • Cisplatin