Mechanism of cadmium-metallothionein-induced nephrotoxicity: relationship to altered renal calcium metabolism.
Prolonged cadmium exposure has been associated with proteinuria, calcuria and loss of calcium from bones in humans. Previous studies have shown that kidney uptake of cadmium in vivo results from proximal tubule absorption of the circulating cadmium metallothionein complex (CdMT), and intracellular release of the Cd2+ ion prior to induction of renal metallothionein. Parenteral administration of CdMT has been found to selectively damage the proximal tubule cell lysosome system with development of a tubular proteinuria pattern similar to that observed under chronic exposure conditions. The present studies also demonstrate a concomitant calcuria but no changes in the excretion of other electrolytes or glucose using this model. These marked changes in renal calcium metabolism occurred in the absence of mitochondrial damage, changes in total, Na/K or Mg-stimulated ATPase activities, renal ATP levels, membrane 45Ca2+ transport or overt tubule cell necrosis during an 8 hour period following CdMT injection. Proteinuria and calcuria were prevented by prior zinc induction of the renal MT pool. Data from these studies indicate that renal proximal tubule cell uptake and degradation of the circulating CdMT complex produces both a marked proteinuria and calcuria. The calcuria does not appear to stem from changes in renal energy metabolism or membrane transport of this element but is probably a secondary result of calcium binding to excreted proteins which are increased in urine to a similar extent. The studies also suggest that zinc status and maintenance of the renal ZnMT pool may play an important role in regulating cadmium-induced renal proteinuria and calcuria by preventing Cd2+ perturbation of the proximal tubule cell lysosome system.
Fowler
B A
BA
National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Goering
P L
PL
Squibb
K S
KS
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D017301:Ca(2+) Mg(2+)-ATPase / Q000378:metabolism; D002118:Calcium / Q000378:metabolism* / Q000652:urine; D002462:Cell Membrane / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008668:Metallothionein / Q000096:biosynthesis / Q000493:pharmacokinetics / Q000633:toxicity*; D008928:Mitochondria / Q000648:ultrastructure; D011507:Proteinuria / Q000139:chemically induced / Q000378:metabolism; D051381:Rats; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D015032:Zinc / Q000494:pharmacology
C004203:cadmium-binding protein; D000255:Adenosine Triphosphate; D008668:Metallothionein; D017301:Ca(2+) Mg(2+)-ATPase; D000254:Sodium-Potassium-Exchanging ATPase; D015032:Zinc; D002118:Calcium