title: Silver ion (Ag+)-induced increases in cell membrane K+ and Na+ permeability in the renal proximal tubule: reversal by thiol reagents.
abstract: The initial mechanisms of injury to the proximal tubule following exposure to nephrotoxic heavy metals are not well established. We studied the immediate effects of silver (Ag+) on K+ transport and respiration with extracellular K+ and O2 electrodes in suspensions of renal cortical tubules. Addition of silver nitrate (AgNO3) to tubules suspended in bicarbonate Ringer's solution caused a rapid, dose-dependent net K+ efflux (Km = 10(-4) M, Vmax = 379 nmol K+/min/mg protein) which was not inhibited by furosemide, barium chloride, quinine, tetraethylammonium, or tolbutamide. An increase in the ouabain-sensitive oxygen consumption rate (QO2) (13.9 +/- 1.1 to 25.7 +/- 4.4 nmol O2/min/mg, P less than 0.001), was observed 19 sec after the K+ efflux induced by AgNO3 (10(-4) M), suggesting a delayed increase in Na+ entry into the cell. Ouabain-insensitive QO2, nystatin-stimulated QO2, and CCCP-uncoupled QO2 were not significantly affected, indicating preserved function of the Na+,K+-ATPase and mitochondria. External addition of the thiol reagents dithiothreitol (1 mM) and reduced glutathione (1 mM) prevented and/or immediately reversed the effects on K+ transport and QO2. We conclude that Ag+ causes early changes in the permeability of the cell membrane to K+ and then to Na+ at concentrations that do not limit Na+,K+-ATPase activity or mitochondrial function. These alterations are likely the result of a reversible interaction of Ag+ with sulfhydryl groups of cell membrane proteins and may represent initial cytotoxic effects common to other sulfhydryl-reactive heavy metals on the proximal tubule.
authors: Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors: B C
authors: BC
authors: Kone
authors: M
authors: M
authors: Kaleta
authors: S R
authors: SR
authors: Gullans
mesh_terms: D000818:Animals; D001464:Barium / Q000494:pharmacology; D002463:Cell Membrane Permeability / Q000187:drug effects*; D005260:Female; D005665:Furosemide / Q000494:pharmacology; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D007700:Kinetics; D010101:Oxygen Consumption / Q000187:drug effects; D011188:Potassium / Q000378:metabolism*; D011803:Quinine / Q000494:pharmacology; D011817:Rabbits; D012835:Silver Nitrate / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism*; D013439:Sulfhydryl Reagents / Q000494:pharmacology*; D014044:Tolbutamide / Q000494:pharmacology
chemical_list: D007473:Ion Channels; D013439:Sulfhydryl Reagents; D001464:Barium; D005665:Furosemide; D012835:Silver Nitrate; D014044:Tolbutamide; D012964:Sodium; D011803:Quinine; D011188:Potassium