Segment-specific and direction-dependent transport of cadmium and manganese in immortalized S1, S2, and S3 cells derived from mouse kidney proximal tubules

Abstract

The kidney proximal tubule is a target of many renal toxicants, including cadmium (Cd), and also a place of reabsorption of essential metals in glomerular filtrate to systemic circulation. Although the mechanisms of metal transport in the convoluted proximal tubule (S1 and S2 segments) and the straight proximal tubule (S3 segment) may differ, little is known about the segment-specific modes of metal transport. Here, we utilized immortalized cell lines derived from the S1, S2, and S3 segments of mouse kidney proximal tubules, and examined the segment-specific and direction-dependent transport of Cd and manganese (Mn) using a trans-well culture system. The results showed that the uptakes of Cd²⁺ and Mn²⁺ from apical sides were the highest in S3 cells, and Cd²⁺, Mn²⁺, and Zn²⁺ mutually inhibited the apical uptake of each metal. As the expression of ZIP8, a zinc transporter having affinities for Cd²⁺ and Mn²⁺, was the highest in S3 cells, ZIP8 may contribute largely to the apical uptakes of these metals. The efficient uptake of Mn²⁺ from apical side of S3 cells may suggest an important role of ZIP8 in proximal tubule in reabsorption of Mn, an essential metal. Our study demonstrated that S1, S2, and S3 cells provide a useful tool for studying the segment-specific and direction-dependent transport of both toxic and essential metals in the kidney’s proximal tubules.