Nephrotoxicity and the Proximal Tubule

Abstract

Cadmium (Cd2+) is a non-essential heavy metal, which is taken up from the environment into the body through pulmonary and enteral pathways. The S1 segment of the kidney proximal tubule (PT) is a major target of chronic Cd2+ toxicity. Renal dysfunction develops in up to 7% of the general population and in its most severe form displays major features of Fanconi syndrome, such as a defective protein, amino acid, glucose, bicarbonate and phosphate reabsorption. The major pathway for Cd2+ uptake by PT cells (PTCs) in vivo is apical endocytosis of Cd2+ complexed to the high-affinity metal-binding protein metallothionein (MT), which may be receptor-mediated. MT is subsequently degraded in endo-lysosomes, and Cd2+ is liberated for translocation into the cytosolic compartment, possibly using transporters for Fe2+, Zn2+ or Cu2+, such as the divalent metal transporter DMT1. Free Cd2+ ions in the extracellular space are translocated across apical and/or basolateral PTC membranes into the cytosol via transporters, whose identity remains unknown. Cytosolic Cd2+ generates reactive oxygen species (ROS), which deplete endogenous radical scavengers. ROS also damage a variety of transport proteins, including the Na+/K+-ATPase, which are subsequently degraded by the proteasome and endo-lysosomal proteases. Cd2+ causes mitochondrial swelling and release of cytochrome c. If these ROS-mediated stress events are not balanced by repair processes, affected cells undergo apoptosis. But Cd2+ also induces the upregulation of cytoprotective stress and metal-scavenging proteins, such as MT. In addition, Cd2+ upregulates the detoxifying pump multidrug resistance P-glycoprotein, which appears to protect PTCs against Cd2+-induced apoptosis. Thus, Cd2+ interferes with various cellular events ranging from mechanisms of induction of programmed cell death to activation of cell survival genes. A better understanding of the cellular mechanisms involved in Cd2+ nephrotoxicity should provide insights into other heavy metal (e.g. Pb2+, Hg2+) nephropathies and various forms of acquired Fanconi syndrome.