MEMBRANE TRANSPORTERS IN EXPERIMENTAL CADMIUM NEPHROTOXICITY

Background and Aims. The symptoms of cadmium (Cd) nephrotoxicity (Cd-NTX) in humans and experimental animals manifest in the defects of reabsorptive and secretory functions of proximal tubules (PT), and include phosphaturia, aminoaciduria, glucosuria, proteinuria, increased excretion of organic anions and cations, and polyuria. These symptoms indicate that Cd targets various transporters in the PT brush-border (BBM) and basolateral (BLM) membrane. The aim of this study is to characterize the expression of these transporters in experimental subchronic and acute model of Cd-NTX in rats. Methods. Cd-NTX was induced by treating rats s.c. with CdCl2 (2 mg Cd/kg b.m./day for 14 days ; subchronic model) or Cd-metallothionein (CdMT ; a single dose of 0.4 mg Cd/kg b.m. 6 or 12 hours before sacrifice ; acute model). Control animals were vehicle-treated. Various methods (immunocytochemistry, Western blotting, transmission and immunogold microscopy, end-point RT-PCR) were applied to study the expression of transporters localized in the PT BBM (VATPase, NaPi2, megalin, NHE3, SGLT1, SGLT2), BLM (Na/K-ATPase, OAT1, OAT3, OCT1, OCT2), or in both membranes (AQP1). Results. In both models of Cd-NTX, PT exhibited loss of BBM and BLM. In subchronic model, the expression of specific transporters was strongly downregulated at the level of protein and mRNA. In acute model we observed: a) time-dependent loss of various BBM transporters and their accumulation in the randomly scattered intracellular vesicles, b) redistribution of NHE3 into the BLM, and c) time-dependent loss of various BLM transporters, and their redistribution in intracellular vesicles that accumulated in the cell subapical domain. Conclusions. The data indicate that the functional defects of PT in Cd-NTX result from: a) loss of absorptive and secretory surface, b) loss of transporting proteins in BBM and BLM, and c) loss of cell polarity. In subchronic Cd-NTX, loss of membrane transporters is largely mRNA-related, whereas in acute Cd-NTX, loss of membrane transporters due to derranged intracellular vesicle trafficking seems to be the major phenomenon.