Comparing Gene Expression during Cadmium Uptake and Distribution: Untreated versus Oral Cd-Treated Wild-Type and ZIP14 Knockout Mice

Abstract

The nonessential metal cadmium (Cd) is toxic only after entering the cell. Proteins possibly relevant to intracellular Cd accumulation include the divalent metal transporter-1 (DMT1) and all 14 zinc-like iron-like protein (ZIP) importers, 10 zinc transporter (ZnT) exporters, and metallothionein chaperones MT1 and MT2. Comparing oral Cd-treated ZIP14 knockout (KO) with wild-type (WT) mice, we predicted Cd uptake and distribution would be diminished in the KO-because ZIP14 is very highly expressed in GI tract and liver; this was indeed observed for Cd content in liver. However, the reverse was found in kidney and lung from 6 or 12 h through 10 days of Cd exposure; at these times, Cd accumulation was unexpectedly greater in KO than WT mice; mRNA levels of the 27 above-mentioned genes were thus examined in proximal small intestine (PSI) versus kidney to see if these paradoxical effects could be explained by substantial alterations in any of the other 26 genes. PSI genes highly expressed in untreated WT animals included seven ZIP and five ZnT transporters, DMT1, MT1, and MT2; kidney genes included 11 ZIP and 7 ZnT transporters, DMT1, MT1, and MT2. Over 10 days of oral Cd, a bimodal response was seen for Cd content in PSI and for various mRNAs; initially, acute effects caused by the toxic metal; subsequently, the up- or down-regulation of important genes presumably to combat the sustained adversity. These data underscore the complex interplay between the gastrointestinal tract and renal proteins that might be relevant to Cd uptake and distribution in animals exposed to oral Cd.

Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism–dystonia

“…As the main regulatory organ involved in Mn homeostasis in humans, the liver seems most likely to play the crucial role in the disease mechanism. Slc39a14 −/− mice furthermore show transcriptional upregulation of Slc30a10 expression, suggesting that Slc30a10 and Slc39a14 transporters indeed act in partnership for efficient hepatic Mn detoxification 52 . We postulate that loss-of-function mutations in SLC39A14 in humans lead to impaired hepatic Mn uptake with resultant hypermanganesemia and downstream neurotoxic effects ( Fig.…”

“…Both of these transporters transport Mn and Fe interdependently 26 30 . A recent study of Slc39a14 −/− mice suggests that Slc39a14 is also instrumental in the uptake of Cd into the liver with hepatic Cd levels being diminished while other organs including kidney, gut and lung showing Cd accumulation 52 .…”

Dietary Cadmium Intake and Its Effects on Kidneys

“…Dietary Cd is taken up by the same transporter systems that the body uses to acquire calcium, iron, zinc, and manganese. These transporters may include divalent metal transporter1 (DMT1), Zrt- and Irt-related protein 14 (ZIP14, a member zinc transporter family), the Ca 2+ -selective channel transient receptor potential vanilloid6 (TRPV6), and human neutrophil gelatinase-associated lipocalin (hNGAL) receptor [ 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. Cd bound to peptides, small proteins, and phytochelatin may be directly absorbed via transcytosis [ 30 , 31 ].…”

“…Animal and in vitro studies suggest that the absorption of Cd in the gastrointestinal tract is mediated by several transporter systems, which may include divalent metal transporter1, DMT1, Zrt- and Irt-related protein (ZIP) of zinc transporter family, namely ZIP14, and the Ca 2+ -selective channel, TRPV6 [ 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. There is also evidence for absorption of dietary Cd by transcytosis mediated by the human neutrophil gelatinase-associated lipocalin (hNGAL) receptor [ 31 ].…”

Targeting Iron Homeostasis in Acute Kidney Injury

“…28 Research has suggested that iron competes with copper and/or manganese for reabsorption, which is evidence for the involvement of zinc and zinclike iron-like (ZIP) transporters in kidney-mediated iron uptake. 29 ZIP8 and ZIP14 are the two zinc transporters that are expressed in proximal tubules. 30 There are several other receptors and transporters that are believed to facilitate iron uptake in the kidney including the lactoferrin receptor, neutrophil gelatinase-associated lipocalin (NGAL) receptor, proton-coupled folate transporter, and mucolipin 1 and 2.…”