{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T19:34:55Z","timestamp":1791315295916,"version":"4.3.1"},"reference-count":7,"publisher":"S. Karger AG","issue":"4","license":[{"start":{"date-parts":[[2003,5,9]],"date-time":"2003-05-09T00:00:00Z","timestamp":1052438400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.karger.com\/Services\/SiteLicenses"},{"start":{"date-parts":[[2003,5,9]],"date-time":"2003-05-09T00:00:00Z","timestamp":1052438400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.karger.com\/Services\/SiteLicenses"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nephron Physiol"],"abstract":"Cadmium (Cd<sup>2+<\/sup>) 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 Cd<sup>2+<\/sup> 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 Cd<sup>2+<\/sup> uptake by PT cells (PTCs) in vivo is apical endocytosis of Cd<sup>2+<\/sup> complexed to the high-affinity metal-binding protein metallothionein (MT), which may be receptor-mediated. MT is subsequently degraded in endo-lysosomes, and Cd<sup>2+<\/sup> is liberated for translocation into the cytosolic compartment, possibly using transporters for Fe<sup>2+<\/sup>, Zn<sup>2+<\/sup> or Cu<sup>2+<\/sup>, such as the divalent metal transporter DMT1. Free Cd<sup>2+<\/sup> ions in the extracellular space are translocated across apical and\/or basolateral PTC membranes into the cytosol via transporters, whose identity remains unknown. Cytosolic Cd<sup>2+<\/sup> generates reactive oxygen species (ROS), which deplete endogenous radical scavengers. ROS also damage a variety of transport proteins, including the Na<sup>+<\/sup>\/K<sup>+<\/sup>-ATPase, which are subsequently degraded by the proteasome and endo-lysosomal proteases. Cd<sup>2+<\/sup> causes mitochondrial swelling and release of cytochrome <i>c<\/i>. If these ROS-mediated stress events are not balanced by repair processes, affected cells undergo apoptosis. But Cd<sup>2+<\/sup> also induces the upregulation of cytoprotective stress and metal-scavenging proteins, such as MT. In addition, Cd<sup>2+<\/sup> upregulates the detoxifying pump multidrug resistance P-glycoprotein, which appears to protect PTCs against Cd<sup>2+<\/sup>-induced apoptosis. Thus, Cd<sup>2+<\/sup> 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 Cd<sup>2+<\/sup> nephrotoxicity should provide insights into other heavy metal (e.g. Pb<sup>2+<\/sup>, Hg<sup>2+<\/sup>) nephropathies and various forms of acquired Fanconi syndrome.<\/jats:p>","DOI":"10.1159\/000070241","type":"journal-article","created":{"date-parts":[[2003,5,28]],"date-time":"2003-05-28T07:40:46Z","timestamp":1054107646000},"page":"p87-p93","source":"Crossref","is-referenced-by-count":225,"title":["Nephrotoxicity and the Proximal Tubule"],"prefix":"10.1159","volume":"93","author":[{"given":"Frank","family":"Th\u00e9venod","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"127","published-online":{"date-parts":[[2003,5,9]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.39.1.267"},{"key":"ref2","doi-asserted-by":"publisher","DOI":"10.1038\/41343"},{"key":"ref3","doi-asserted-by":"publisher","DOI":"10.1006\/toxs.1998.2541"},{"key":"ref4","doi-asserted-by":"publisher","DOI":"10.1007\/s002040050562"},{"key":"ref5","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.3.1887"},{"key":"ref6","doi-asserted-by":"publisher","DOI":"10.1080\/15287390151101583"},{"key":"ref7","doi-asserted-by":"publisher","DOI":"10.1006\/taap.1997.8125"}],"container-title":["Nephron Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.karger.com\/Article\/Pdf\/70241","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.karger.com\/Article\/Pdf\/70241","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T03:19:02Z","timestamp":1745464742000},"score":1,"resource":{"primary":{"URL":"https:\/\/karger.com\/article\/doi\/10.1159\/000070241"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2003,5,9]]},"references-count":7,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2003,4,1]]}},"URL":"https:\/\/doi.org\/10.1159\/000070241","archive":["Portico"],"relation":{},"ISSN":["1660-2137"],"issn-type":[{"value":"1660-2137","type":"electronic"}],"subject":[],"published":{"date-parts":[[2003,5,9]]}}}