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Articles in PresS, published online ahead of print July 30, 2002
Am J Physiol Renal Physiol, 10.1152/ajprenal.00066.2002
Submitted on February 15, 2002
Accepted on July 25, 2002
1 Unit of Molecular Toxicology, Institute for Medical Research and Occupational Health, Zagreb, Croatia (Hrvatska)
2 Program in Membrane Biology and Renal Unit, Massachusetts General Hospital, Charlestown, MA, USA
* To whom correspondence should be addressed. E-mail: sabolic{at}imi.hr.
Nephrotoxicity in humans and experimental animals due to chronic exposure to cadmium (Cd) is manifested by defects in the reabsorptive and secretory functions of proximal tubules (PT). The main symptoms of Cd nephrotoxicity, including polyuria, phosphaturia, aminoaciduria,
glucosuria, and proteinuria, suggest that various brush-border membrane (BBM) transporters are the main targets of Cd. Specific transporters may be either directly inhibited by Cd or lost from the BBM following Cd-treatment, or both. We have recently proposed that Cd may impair the vesicle-dependent recycling of BBM transporters by inhibiting vacuolar H+ -ATPase (V-ATPase) activity and endocytosis in PT cells (Kidney Int. 53:1713-1726, 1998). The mechanism underlying the Cd effect was further explored in an in vivo model of experimental Cd-nephrotoxicity induced by Cd-metallothionein (CdMT; 0.4 mg Cd/kg b.m., a single dose s.c.) in rats. The time-dependent redistribution of various BBM transporters was examined in this model by fluorescence and gold-labeling immunocytochemistry on tissue sections, and by immunoblotting of isolated renal cortical BBM. In PT cells of CdMT-treated rats we observed: a) shortening and loss of microvilli, b) time-dependent loss of megalin, V-ATPase, aquaporin 1 (AQP1), and type 3 Na+/H+ exchanger (NHE3) from the BBM, c) redistribution of these transporters into vesicles that were randomly scattered throughout the cell cytoplasm, and d) redistribution of NHE3, but not megalin, into the basolateral plasma
membrane. The internalization of BBM transporters was accompanied by fragmentation and loss of microtubules, and by an increased abundance of 
-tubulin monomers in PT cells. Transporter redistribution was detectable as early as 1 h following CdMT treatment and increased in magnitude over the next 12 h. We conclude that the early mechanism of Cd toxicity in PT cells may include a colchicine-like depolymerization of microtubules and impaired vesicle-dependent recycling of various BBM protiens. These processes may lead to a time-dependent loss of cell membrane components, resulting in reabsorptive and secretary defects that occur in Cd-induced nephrotoxicity.
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