Differential actions of cisplatin on renal proximal tubule and inner medullary collecting duct cells.
Cisplatin (CP) nephrotoxicity in vivo is characterized by proximal tubule (PT) and collecting duct dysfunction. We reported previously that mitochondrial injury is an important early event in CP toxicity to PT cells and precedes inhibition of Na+,K(+)-ATPase activity and loss of cell K+. In the present study, we monitored oxygen consumption (QO2) and net K+ fluxes in intact inner medullary collecting duct (IMCD) and PT cells in vitro, using O2- and K(+)-sensitive electrodes, to determine if CP has similar effects on IMCD cells. Short-term exposure of IMCD cells to CP resulted in inhibition of spontaneous, ouabain-sensitive and ouabain-oversensitive QO2, but to a lesser degree than in PT. Ouabain-sensitive K+ transport and cell K+ content were also reduced in intact IMCD cells in this setting, confirming inhibition of Na+,K(+)-ATPase activity. In contrast, Na+,K(+)-ATPase activity measured in IMCD cell lysates was not altered. These results suggested that CP inhibited Na+,K(+)-ATPase activity in intact IMCD cells indirectly either by blocking Na+ entry or by inhibiting mitochondrial oxidative phosphorylation. Nystatin (Na+ ionophore) and carbonyl cyanide m-chlorophenylhydrazone (CCCP, uncoupler of oxidative phosphorylation) were used to distinguish between these possibilities. Nystatin-stimulated and CCCP-uncoupled QO2 were reduced in CP-treated IMCD cells by 34 +/- 10% and 25 +/- 5%, respectively, indicating mitochondrial injury. Again, the effects of CP on nystatin-stimulated and CCCP-uncoupled QO2 in IMCD cells were significantly less dramatic than in PT cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Brady
H R
HR
Renal Division, Brigham & Women's Hospital, Boston, Massachusetts.
Zeidel
M L
ML
Kone
B C
BC
Giebisch
G
G
Gullans
S R
SR
D000818:Animals; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology*; D005260:Female; D007685:Kidney Tubules, Collecting / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D015227:Lipid Peroxidation; D008315:Malondialdehyde / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D011817:Rabbits; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
D008315:Malondialdehyde; D000254:Sodium-Potassium-Exchanging ATPase; D002945:Cisplatin; D011188:Potassium; D010100:Oxygen