Sulfhydryl-reactive heavy metals increase cell membrane K+ and Ca2+ transport in renal proximal tubule.
The cellular mechanisms by which nephrotoxic heavy metals injure the proximal tubule are incompletely defined. We used extracellular electrodes to measure the early effects of heavy metals and other sulfhydryl reagents on net K+ and Ca2+ transport and respiration (QO2) of proximal tubule suspensions. Hg2+, Cu2+, and Au3+ (10(-4)M) each caused a rapid net K+ efflux and a delayed inhibition of QO2. The Hg2(+)-induced net K+ release represented passive K+ transport and was not inhibited by barium, tetraethylammonium, or furosemide. Both Hg2+ and Ag+ promoted a net Ca2+ uptake that was nearly coincident with the onset of the net K+ efflux. A delayed inhibition of ouabain-sensitive QO2 and nystatin-stimulated QO2, indicative of Na+, K(+)-ATPase inhibition, was observed after 30 sec of exposure to Hg2+. More prolonged treatment (2 min) of the tubules with Hg2+ resulted in a 40% reduction in the CCCP-uncoupled QO2, indicating delayed injury to the mitochondria. The net K+ efflux was mimicked by the sulfhydryl reagents pCMBS and N-ethylmale-imide (10(-4) M) and prevented by dithiothreitol (DTT) or reduced glutathione (GSH) (10(-4) M). In addition, both DTT and GSH immediately reversed the Ag(+)-induced net Ca2+ uptake. Thus, sulfhydryl-reactive heavy metals cause rapid, dramatic changes in the membrane ionic permeability of the proximal tubule before disrupting Na+, K(+)-ATPase activity or mitochondrial function. These alterations appear to be the result of an interaction of the metal ions with sulfhydryl groups of cell membrane proteins responsible for the modulation of cation permeability.
Kone
B C
BC
Renal Division, Brigham and Women's Hospital, Boston, Massachusetts.
Brenner
R M
RM
Gullans
S R
SR
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003300:Copper / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D005260:Female; D005978:Glutathione / Q000494:pharmacology; D006046:Gold / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism*; D008628:Mercury / Q000494:pharmacology; D008670:Metals / Q000494:pharmacology*; D010042:Ouabain / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects; D011188:Potassium / Q000378:metabolism*; D011817:Rabbits; D012964:Sodium / Q000378:metabolism; D013439:Sulfhydryl Reagents / Q000494:pharmacology*
D008670:Metals; D013439:Sulfhydryl Reagents; D010042:Ouabain; D006046:Gold; D003300:Copper; D012964:Sodium; D008628:Mercury; D005978:Glutathione; D011188:Potassium; D002118:Calcium; D004229:Dithiothreitol