Cadmium transporters in the kidney and cadmium-induced nephrotoxicity

Abstract

Among the organs in which the environmental pollutant cadmium causes toxicity, the kidney has gained the most attention in recent years. Numerous studies have sought to unravel the exact pathways by which cadmium enters the renal epithelial cells and the mechanisms by which it causes toxicity in the kidney. The purpose of this review is to present the progress made on the mechanisms of cadmium transport in the kidney and the role of transporter proteins in cadmium-induced nephrotoxicity.

Figure 1

Cadmium transporters. Cadmium (Cd) is mostly bound to albumin in the circulation after absorption and then taken up by the liver. Some cadmium is bound to thiol-containing groups such as glutathione (GSH) and l-cysteine (Cys), which may be absorbed through both basolateral and apical sides of renal proximal tubular (PT) cells. In the liver, cadmium stimulates the synthesis of metallothioneins (MTs) and forms the Cd–MT complex to be released into the circulation. Cd–MT is easily filtered through the glomerulus and reabsorbed into PT segment 1 (S1) and segment 2 (S2) via endocytosis. Multiple transporters are responsible for the transport of free cadmium ions in different PT segments, distal convolute tubular, and connected tubular cells, either from the blood to the epithelial cells or from the epithelial cells to the urine. Alb, albumin; MT, metallothionein; GSH, glutathione; Cys, l-cysteine; PT, proximal tubular; DCT, distal convoluted tubular; CT, connected tubular; Cd²⁺, cadmium ion; OCT, organic cation transporter; MATE, multidrug and toxin extrusion proteins; P-gp, P-glycoprotein; Zip 8, zinc/iron-regulated transporter 8; Zip 14, zinc/iron-regulated transporter 14; DMT1, divalent metal-ion transporter-1; TRVP5, transient receptor potential vanilloid type 5; VDCC, voltage-dependent calcium channels. The small black arrows indicate the direction of Cd transporters in the kidney. Our unpublished data [4] suggest a role of MATE in Cd transport, which needs to be further characterized (indicated by a question marker). The white arrows indicate the direction of Cd transport between blood and either renal glomerulus or hepatocytes, with the size showing the relative contribution from different Cd complexes.