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Prof. Frank Thévenod
Universitat Witten/Herdecke, Department of Physiology, Pathophysiology & Toxicology, Witten, Germany

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0 Cancer Biology
0 Iron
0 Signal Transduction
0 Cadmium
0 Metal ions

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Cadmium
Iron
Metal ions
Signal Transduction
Membrane transport

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Journal article
Published: 06 July 2021 in International Journal of Molecular Sciences
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Background: The proximal tubule (PT) is the major target of cadmium (Cd2+) nephrotoxicity. Current dogma postulates that Cd2+ complexed to metallothionein (MT) (CdMT) is taken up through receptor-mediated endocytosis (RME) via the PT receptor megalin:cubilin, which is the predominant pathway for reuptake of filtered proteins in the kidney. Nevertheless, there is evidence that the distal parts of the nephron are also sensitive to damage induced by Cd2+. In rodent kidneys, another receptor for protein endocytosis, the 24p3 receptor (24p3R), is exclusively expressed in the apical membranes of distal tubules (DT) and collecting ducts (CD). Cell culture studies have demonstrated that RME and toxicity of CdMT and other (metal ion)–protein complexes in DT and CD cells is mediated by 24p3R. In this study, we evaluated the uptake of labeled CdMT complex through 24p3R after acute kidney injury (AKI) induced by gentamicin (GM) administration that disrupts PT function. Subcutaneous administration of GM at 10 mg/kg/day for seven days did not alter the structural and functional integrity of the kidney’s filtration barrier. However, because of PT injury, the concentration of the renal biomarker Kim-1 increased. When CdMT complex coupled to FITC was administered intravenously, both uptake of the CdMT complex and 24p3R expression in DT increased and also colocalized after PT injury induced by GM. Although megalin decreased in PT after GM administration, urinary protein excretion was not changed, which suggests that the increased levels of 24p3R in the distal nephron could be acting as a compensatory mechanism for protein uptake. Altogether, these results suggest that PT damage increases the uptake of the CdMT complex through 24p3R in DT (and possibly CD) and compensate for protein losses associated with AKI.

ACS Style

Itzel Zavala-Guevara; Manolo Ortega-Romero; Juana Narváez-Morales; Tania Jacobo-Estrada; Wing-Kee Lee; Laura Arreola-Mendoza; Frank Thévenod; Olivier Barbier. Increased Endocytosis of Cadmium-Metallothionein through the 24p3 Receptor in an In Vivo Model with Reduced Proximal Tubular Activity. International Journal of Molecular Sciences 2021, 22, 7262 .

AMA Style

Itzel Zavala-Guevara, Manolo Ortega-Romero, Juana Narváez-Morales, Tania Jacobo-Estrada, Wing-Kee Lee, Laura Arreola-Mendoza, Frank Thévenod, Olivier Barbier. Increased Endocytosis of Cadmium-Metallothionein through the 24p3 Receptor in an In Vivo Model with Reduced Proximal Tubular Activity. International Journal of Molecular Sciences. 2021; 22 (14):7262.

Chicago/Turabian Style

Itzel Zavala-Guevara; Manolo Ortega-Romero; Juana Narváez-Morales; Tania Jacobo-Estrada; Wing-Kee Lee; Laura Arreola-Mendoza; Frank Thévenod; Olivier Barbier. 2021. "Increased Endocytosis of Cadmium-Metallothionein through the 24p3 Receptor in an In Vivo Model with Reduced Proximal Tubular Activity." International Journal of Molecular Sciences 22, no. 14: 7262.

Molecular toxicology
Published: 28 June 2021 in Archives of Toxicology
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The liver hormone hepcidin regulates systemic iron homeostasis. Hepcidin is also expressed by the kidney, but exclusively in distal nephron segments. Several studies suggest hepcidin protects against kidney damage involving Fe2+ overload. The nephrotoxic non-essential metal ion Cd2+ can displace Fe2+ from cellular biomolecules, causing oxidative stress and cell death. The role of hepcidin in Fe2+ and Cd2+ toxicity was assessed in mouse renal cortical [mCCD(cl.1)] and inner medullary [mIMCD3] collecting duct cell lines. Cells were exposed to equipotent Cd2+ (0.5–5 μmol/l) and/or Fe2+ (50–100 μmol/l) for 4–24 h. Hepcidin (Hamp1) was transiently silenced by RNAi or overexpressed by plasmid transfection. Hepcidin or catalase expression were evaluated by RT-PCR, qPCR, immunoblotting or immunofluorescence microscopy, and cell fate by MTT, apoptosis and necrosis assays. Reactive oxygen species (ROS) were detected using CellROX™ Green and catalase activity by fluorometry. Hepcidin upregulation protected against Fe2+-induced mIMCD3 cell death by increasing catalase activity and reducing ROS, but exacerbated Cd2+-induced catalase dysfunction, increasing ROS and cell death. Opposite effects were observed with Hamp1 siRNA. Similar to Hamp1 silencing, increased intracellular Fe2+ prevented Cd2+ damage, ROS formation and catalase disruption whereas chelation of intracellular Fe2+ with desferrioxamine augmented Cd2+ damage, corresponding to hepcidin upregulation. Comparable effects were observed in mCCD(cl.1) cells, indicating equivalent functions of renal hepcidin in different collecting duct segments. In conclusion, hepcidin likely binds Fe2+, but not Cd2+. Because Fe2+ and Cd2+ compete for functional binding sites in proteins, hepcidin affects their free metal ion pools and differentially impacts downstream processes and cell fate.

ACS Style

Stephanie Probst; Johannes Fels; Bettina Scharner; Natascha A. Wolff; Eleni Roussa; Rachel P. L. van Swelm; Wing-Kee Lee; Frank Thévenod. Role of hepcidin in oxidative stress and cell death of cultured mouse renal collecting duct cells: protection against iron and sensitization to cadmium. Archives of Toxicology 2021, 95, 1 -17.

AMA Style

Stephanie Probst, Johannes Fels, Bettina Scharner, Natascha A. Wolff, Eleni Roussa, Rachel P. L. van Swelm, Wing-Kee Lee, Frank Thévenod. Role of hepcidin in oxidative stress and cell death of cultured mouse renal collecting duct cells: protection against iron and sensitization to cadmium. Archives of Toxicology. 2021; 95 (8):1-17.

Chicago/Turabian Style

Stephanie Probst; Johannes Fels; Bettina Scharner; Natascha A. Wolff; Eleni Roussa; Rachel P. L. van Swelm; Wing-Kee Lee; Frank Thévenod. 2021. "Role of hepcidin in oxidative stress and cell death of cultured mouse renal collecting duct cells: protection against iron and sensitization to cadmium." Archives of Toxicology 95, no. 8: 1-17.

Correction
Published: 19 April 2021 in Frontiers in Cell and Developmental Biology
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A Corrigendum on Iron and Cadmium Entry Into Renal Mitochondria: Physiological and Toxicological Implications by Thévenod, F., Lee, W.-K., and Garrick, M. D. (2020). Front. Cell Dev. Biol. 8:848. doi: 10.3389/fcell.2020.00848 In the published article, there was an error in the Funding statement for MG. The corrected paragraph appears below: FT received funding from BMBF (01DN16039), DFG (TH345), and ZBAF. MG appreciates the support of grant R01 DK109717 from the National Institute of Diabetes and Digestive and Kidney Diseases and the Office of Dietary Supplements. W-KL received financial support through the Intramural Funding Program at Witten/Herdecke University (IFF 2018-52). The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated. Keywords: reactive oxygen species, divalent metal transporter 1, ionic mimicry, manganese, copper, nephrotoxicity, acute kidney injury, chronic kidney disease Citation: Thévenod F, Lee W-K and Garrick MD (2021) Corrigendum: Iron and Cadmium Entry Into Renal Mitochondria: Physiological and Toxicological Implications. Front. Cell Dev. Biol. 9:687810. doi: 10.3389/fcell.2021.687810 Received: 30 March 2021; Accepted: 31 March 2021; Published: 19 April 2021. Approved by: Copyright © 2021 Thévenod, Lee and Garrick. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Frank Thévenod, [email protected]

ACS Style

Frank Thévenod; Wing-Kee Lee; Michael D. Garrick. Corrigendum: Iron and Cadmium Entry Into Renal Mitochondria: Physiological and Toxicological Implications. Frontiers in Cell and Developmental Biology 2021, 9, 687810 .

AMA Style

Frank Thévenod, Wing-Kee Lee, Michael D. Garrick. Corrigendum: Iron and Cadmium Entry Into Renal Mitochondria: Physiological and Toxicological Implications. Frontiers in Cell and Developmental Biology. 2021; 9 ():687810.

Chicago/Turabian Style

Frank Thévenod; Wing-Kee Lee; Michael D. Garrick. 2021. "Corrigendum: Iron and Cadmium Entry Into Renal Mitochondria: Physiological and Toxicological Implications." Frontiers in Cell and Developmental Biology 9, no. : 687810.

Dataset
Published: 24 November 2020 in Pancreapedia: Exocrine Pancreas Knowledge Base
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ACS Style

Frank Thévenod. Channels and Transporters in Zymogen Granule Membranes and their Role in Granule Function: A Critical Assessment. Pancreapedia: Exocrine Pancreas Knowledge Base 2020, 1 .

AMA Style

Frank Thévenod. Channels and Transporters in Zymogen Granule Membranes and their Role in Granule Function: A Critical Assessment. Pancreapedia: Exocrine Pancreas Knowledge Base. 2020; ():1.

Chicago/Turabian Style

Frank Thévenod. 2020. "Channels and Transporters in Zymogen Granule Membranes and their Role in Granule Function: A Critical Assessment." Pancreapedia: Exocrine Pancreas Knowledge Base , no. : 1.

Review
Published: 02 September 2020 in Frontiers in Cell and Developmental Biology
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Regulation of body fluid homeostasis is a major renal function, occurring largely through epithelial solute transport in various nephron segments driven by Na+/K+-ATPase activity. Energy demands are greatest in the proximal tubule and thick ascending limb where mitochondrial ATP production occurs through oxidative phosphorylation. Mitochondria contain 20–80% of the cell’s iron, copper, and manganese that are imported for their redox properties, primarily for electron transport. Redox reactions, however, also lead to reactive, toxic compounds, hence careful control of redox-active metal import into mitochondria is necessary. Current dogma claims the outer mitochondrial membrane (OMM) is freely permeable to metal ions, while the inner mitochondrial membrane (IMM) is selectively permeable. Yet we recently showed iron and manganese import at the OMM involves divalent metal transporter 1 (DMT1), an H+-coupled metal ion transporter. Thus, iron import is not only regulated by IMM mitoferrins, but also depends on the OMM to intermembrane space H+ gradient. We discuss how these mitochondrial transport processes contribute to renal injury in systemic (e.g., hemochromatosis) and local (e.g., hemoglobinuria) iron overload. Furthermore, the environmental toxicant cadmium selectively damages kidney mitochondria by “ionic mimicry” utilizing iron and calcium transporters, such as OMM DMT1 or IMM calcium uniporter, and by disrupting the electron transport chain. Consequently, unraveling mitochondrial metal ion transport may help develop new strategies to prevent kidney injury induced by metals.

ACS Style

Frank Thévenod; Wing-Kee Lee; Michael D. Garrick. Iron and Cadmium Entry Into Renal Mitochondria: Physiological and Toxicological Implications. Frontiers in Cell and Developmental Biology 2020, 8, 1 .

AMA Style

Frank Thévenod, Wing-Kee Lee, Michael D. Garrick. Iron and Cadmium Entry Into Renal Mitochondria: Physiological and Toxicological Implications. Frontiers in Cell and Developmental Biology. 2020; 8 ():1.

Chicago/Turabian Style

Frank Thévenod; Wing-Kee Lee; Michael D. Garrick. 2020. "Iron and Cadmium Entry Into Renal Mitochondria: Physiological and Toxicological Implications." Frontiers in Cell and Developmental Biology 8, no. : 1.

Review article
Published: 23 March 2020 in Archives of Toxicology
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Ever increasing environmental presence of cadmium as a consequence of industrial activities is considered a health hazard and is closely linked to deteriorating global health status. General animal and human cadmium exposure ranges from ingestion of foodstuffs sourced from heavily polluted hotspots and cigarette smoke to widespread contamination of air and water, including cadmium-containing microplastics found in household water. Cadmium is promiscuous in its effects and exerts numerous cellular perturbations based on direct interactions with macromolecules and its capacity to mimic or displace essential physiological ions, such as iron and zinc. Cell organelles use lipid membranes to form complex tightly-regulated, compartmentalized networks with specialized functions, which are fundamental to life. Interorganellar communication is crucial for orchestrating correct cell behavior, such as adaptive stress responses, and can be mediated by the release of signaling molecules, exchange of organelle contents, mechanical force generated through organelle shape changes or direct membrane contact sites. In this review, cadmium effects on organellar structure and function will be critically discussed with particular consideration to disruption of organelle physiology in vertebrates.

ACS Style

Wing-Kee Lee; Frank Thévenod. Cell organelles as targets of mammalian cadmium toxicity. Archives of Toxicology 2020, 94, 1017 -1049.

AMA Style

Wing-Kee Lee, Frank Thévenod. Cell organelles as targets of mammalian cadmium toxicity. Archives of Toxicology. 2020; 94 (4):1017-1049.

Chicago/Turabian Style

Wing-Kee Lee; Frank Thévenod. 2020. "Cell organelles as targets of mammalian cadmium toxicity." Archives of Toxicology 94, no. 4: 1017-1049.

Journal article
Published: 30 October 2019 in International Journal of Molecular Sciences
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The rodent collecting duct (CD) expresses a 24p3/NGAL/lipocalin-2 (LCN2) receptor (SLC22A17) apically, possibly to mediate high-affinity reabsorption of filtered proteins by endocytosis, although its functions remain uncertain. Recently, we showed that hyperosmolarity/-tonicity upregulates SLC22A17 in cultured mouse inner-medullary CD cells, whereas activation of toll-like receptor 4 (TLR4), via bacterial lipopolysaccharides (LPS), downregulates SLC22A17. This is similar to the upregulation of Aqp2 by hyperosmolarity/-tonicity and arginine vasopressin (AVP), and downregulation by TLR4 signaling, which occur via the transcription factors NFAT5 (TonEBP or OREBP), cAMP-responsive element binding protein (CREB), and nuclear factor-kappa B, respectively. The aim of the study was to determine the effects of osmolarity/tonicity and AVP, and their associated signaling pathways, on the expression of SLC22A17 and its ligand, LCN2, in the mouse (m) cortical collecting duct cell line mCCD(cl.1). Normosmolarity/-tonicity corresponded to 300 mosmol/L, whereas the addition of 50–100 mmol/L NaCl for up to 72 h induced hyperosmolarity/-tonicity (400–500 mosmol/L). RT-PCR, qPCR, immunoblotting and immunofluorescence microscopy detected Slc22a17/SLC22A17 and Lcn2/LCN2 expression. RNAi silenced Nfat5, and the pharmacological agent 666-15 blocked CREB. Activation of TLR4 was induced with LPS. Similar to Aqp2, hyperosmotic/-tonic media and AVP upregulated Slc22a17/SLC22A17, via activation of NFAT5 and CREB, respectively, and LPS/TLR4 signaling downregulated Slc22a17/SLC22A17. Conversely, though NFAT5 mediated the hyperosmolarity/-tonicity induced downregulation of Lcn2/LCN2 expression, AVP reduced Lcn2/LCN2 expression and predominantly apical LCN2 secretion, evoked by LPS, through a posttranslational mode of action that was independent of CREB signaling. In conclusion, the hyperosmotic/-tonic upregulation of SLC22A17 in mCCD(cl.1) cells, via NFAT5, and by AVP, via CREB, suggests that SLC22A17 contributes to adaptive osmotolerance, whereas LCN2 downregulation could counteract increased proliferation and permanent damage of osmotically stressed cells.

ACS Style

Stephanie Probst; Bettina Scharner; Ruairi McErlean; Wing-Kee Lee; Frank Thévenod. Inverse Regulation of Lipocalin-2/24p3 Receptor/SLC22A17 and Lipocalin-2 Expression by Tonicity, NFAT5/TonEBP and Arginine Vasopressin in Mouse Cortical Collecting Duct Cells mCCD(cl.1): Implications for Osmotolerance. International Journal of Molecular Sciences 2019, 20, 5398 .

AMA Style

Stephanie Probst, Bettina Scharner, Ruairi McErlean, Wing-Kee Lee, Frank Thévenod. Inverse Regulation of Lipocalin-2/24p3 Receptor/SLC22A17 and Lipocalin-2 Expression by Tonicity, NFAT5/TonEBP and Arginine Vasopressin in Mouse Cortical Collecting Duct Cells mCCD(cl.1): Implications for Osmotolerance. International Journal of Molecular Sciences. 2019; 20 (21):5398.

Chicago/Turabian Style

Stephanie Probst; Bettina Scharner; Ruairi McErlean; Wing-Kee Lee; Frank Thévenod. 2019. "Inverse Regulation of Lipocalin-2/24p3 Receptor/SLC22A17 and Lipocalin-2 Expression by Tonicity, NFAT5/TonEBP and Arginine Vasopressin in Mouse Cortical Collecting Duct Cells mCCD(cl.1): Implications for Osmotolerance." International Journal of Molecular Sciences 20, no. 21: 5398.

Preprint
Published: 04 September 2019
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The rodent collecting duct (CD) expresses a 24p3/NGAL/lipocalin-2 (Lcn2) receptor (Slc22a17) apically to possibly mediate high-affinity reabsorption of filtered proteins by endocytosis, yet its functions remain uncertain. Recently, we showed that hyperosmolarity/-tonicity upregulates Slc22a17 in cultured mouse inner medullary CD cells, whereas activation of toll-like receptor 4 (TLR4) via bacterial lipopolysaccharides (LPS) downregulates Slc22a17. This is similar to the upregulation of Aqp2 by hyperosmolarity/-tonicity and arginine vasopressin (AVP) and downregulation by TLR4 signaling that occur via the transcription factors Nfat5 (TonEBP or OREBP), cAMP-responsive element binding protein (CREB), and nuclear factor-kappa B, respectively. The aim of the study was to determine the effects of osmolarity/tonicity via Nfat5, AVP via CREB and TLR4 signaling on the expression of Slc22a17 and its ligand Lcn2 in the mouse (m) cortical collecting duct cell line mCCD(cl.1). Normosmolarity/-tonicity was 300 mosmol/l whereas addition of 50-100 mmol/l NaCl for up to 72 h induced hyperosmolarity/-tonicity (400-500 mosmol/l). RT-PCR, qPCR, immunoblotting and immunofluorescence microscopy detected Slc22a17 and Lcn2 expression. RNAi silenced Nfat5, and the pharmacological agent 666-15 blocked CREB. Activation of TLR4 occurred with LPS. Similar to Aqp2, hyperosmotic/-tonic media and AVP upregulated Slc22a17 via activation of Nfat5 and CREB, respectively, and LPS/TLR4 signaling downregulated Slc22a17. Conversely, though Nfat5 mediated hyperosmolarity/-tonicity induced downregulation of Lcn2 expression, AVP reduced Lcn2 expression and predominantly apical Lcn2 secretion evoked by LPS, but through a posttranslational mode of action that was independent of cAMP signaling. In conclusion, the hyperosmotic/-tonic upregulation of Slc22a17 in mCCD(cl.1) cells via Nfat5 and by AVP via CREB suggests a contribution of Slc22a17 to adaptive osmotolerance, whereas Lcn2 downregulation could counteract increased proliferation and permanent damage of osmotically stressed cells.

ACS Style

Stephanie Probst; Bettina Scharner; Wing-Kee Lee; Frank Thévenod. Inverse Regulation of Lipocalin-2/24p3 Receptor/Slc22a17 and Lipocalin-2 Expression by Tonicity, Nfat5/TonEBP and Arginine Vasopressin in Mouse Cortical Collecting Duct Cells mCCD(cl.1): Implications for Osmotolerance. 2019, 1 .

AMA Style

Stephanie Probst, Bettina Scharner, Wing-Kee Lee, Frank Thévenod. Inverse Regulation of Lipocalin-2/24p3 Receptor/Slc22a17 and Lipocalin-2 Expression by Tonicity, Nfat5/TonEBP and Arginine Vasopressin in Mouse Cortical Collecting Duct Cells mCCD(cl.1): Implications for Osmotolerance. . 2019; ():1.

Chicago/Turabian Style

Stephanie Probst; Bettina Scharner; Wing-Kee Lee; Frank Thévenod. 2019. "Inverse Regulation of Lipocalin-2/24p3 Receptor/Slc22a17 and Lipocalin-2 Expression by Tonicity, Nfat5/TonEBP and Arginine Vasopressin in Mouse Cortical Collecting Duct Cells mCCD(cl.1): Implications for Osmotolerance." , no. : 1.

Journal article
Published: 14 May 2019 in International Journal of Molecular Sciences
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Cadmium (Cd2+) in the environment is a significant health hazard. Chronic low Cd2+ exposure mainly results from food and tobacco smoking and causes kidney damage, predominantly in the proximal tubule. Blood Cd2+ binds to thiol-containing high (e.g., albumin, transferrin) and low molecular weight proteins (e.g., the high-affinity metal-binding protein metallothionein, β2-microglobulin, α1-microglobulin and lipocalin-2). These plasma proteins reach the glomerular filtrate and are endocytosed at the proximal tubule via the multiligand receptor complex megalin:cubilin. The current dogma of chronic Cd2+ nephrotoxicity claims that Cd2+-metallothionein endocytosed via megalin:cubilin causes renal damage. However, a thorough study of the literature strongly argues for revision of this model for various reasons, mainly: (i) It relied on studies with unusually high Cd2+-metallothionein concentrations; (ii) the KD of megalin for metallothionein is ~105-times higher than (Cd2+)-metallothionein plasma concentrations. Here we investigated the uptake and toxicity of ultrafiltrated Cd2+-binding protein ligands that are endocytosed via megalin:cubilin in the proximal tubule. Metallothionein, β2-microglobulin, α1-microglobulin, lipocalin-2, albumin and transferrin were investigated, both as apo- and Cd2+-protein complexes, in a rat proximal tubule cell line (WKPT-0293 Cl.2) expressing megalin:cubilin at low passage, but is lost at high passage. Uptake was determined by fluorescence microscopy and toxicity by MTT cell viability assay. Apo-proteins in low and high passage cells as well as Cd2+-protein complexes in megalin:cubilin deficient high passage cells did not affect cell viability. The data prove Cd2+-metallothionein is not toxic, even at >100-fold physiological metallothionein concentrations in the primary filtrate. Rather, Cd2+-β2-microglobulin, Cd2+-albumin and Cd2+-lipocalin-2 at concentrations present in the primary filtrate are taken up by low passage proximal tubule cells and cause toxicity. They are therefore likely candidates of Cd2+-protein complexes damaging the proximal tubule via megalin:cubilin at concentrations found in the ultrafiltrate.

ACS Style

Johannes Fels; Bettina Scharner; Ralf Zarbock; Itzel Pamela Zavala Guevara; Wing-Kee Lee; Olivier C. Barbier; Frank Thévenod. Cadmium Complexed with β2-Microglubulin, Albumin and Lipocalin-2 rather than Metallothionein Cause Megalin:Cubilin Dependent Toxicity of the Renal Proximal Tubule. International Journal of Molecular Sciences 2019, 20, 2379 .

AMA Style

Johannes Fels, Bettina Scharner, Ralf Zarbock, Itzel Pamela Zavala Guevara, Wing-Kee Lee, Olivier C. Barbier, Frank Thévenod. Cadmium Complexed with β2-Microglubulin, Albumin and Lipocalin-2 rather than Metallothionein Cause Megalin:Cubilin Dependent Toxicity of the Renal Proximal Tubule. International Journal of Molecular Sciences. 2019; 20 (10):2379.

Chicago/Turabian Style

Johannes Fels; Bettina Scharner; Ralf Zarbock; Itzel Pamela Zavala Guevara; Wing-Kee Lee; Olivier C. Barbier; Frank Thévenod. 2019. "Cadmium Complexed with β2-Microglubulin, Albumin and Lipocalin-2 rather than Metallothionein Cause Megalin:Cubilin Dependent Toxicity of the Renal Proximal Tubule." International Journal of Molecular Sciences 20, no. 10: 2379.

Journal article
Published: 01 May 2019 in Cancer Letters
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Oncogenic pituitary homeobox 2 (PITX2), a de facto master regulator of developmental organ asymmetry, previously upregulated multidrug resistance (MDR) P-glycoprotein ABCB1 in A498 renal cell carcinoma (RCC) cells. The role of PITX2 isoforms in MDR cancers was investigated. Data mining correlated elevated PITX2 in >30% of cancers analyzed, maximally in colon (4.4-fold), confirmed in co-immunostaining of colon and renal cancer microarrays wherein ABCB1 concomitantly increased in RCC. Drug-resistant colorectal adenocarcinoma Colo320DM cells exhibited increased nuclear PITX2 (40-fold), PITX2 promoter activity (27-fold) and ABCB1 (8000-fold) compared to drug-sensitive Colo205. ABCB1 inhibitor PSC833/valspodar or PITX2 siRNA reversed doxorubicin resistance. Nuclei from Colo320DM and A498 cells harbored PITX2A/B1 and PITX2A/B1/B2/Cα/Cβ, respectively. ChIP-qPCR evidenced PITX2 promoter binding in drug exporters ABCB1, ABCC1, ABCG2 and importer hOCT3/SLC22A3. In A498, 786-O, Caki-1, Colo320DM, and Caco2 cells, PITX2 siRNA diminished exporters, increased hOCT3/SLC22A3 expression and activity, and reverted vincristine resistance. Heterologous PITX2 expression induced ABCB1, repressed hOCT3/SLC22A3, enhanced vincristine resistance and diminished proliferation inhibition wherein PITX2A and PITX2C were most effective. Furthermore, PITX2 activity and MDR depended on phosphorylation by GSK3 in A498 cells. Conclusively, oncogenic PITX2 limits sensitizing drug uptake and potentiates cytoprotective drug efflux, contributing to MDR phenotype.

ACS Style

Wing-Kee Lee; Frank Thévenod. Oncogenic PITX2 facilitates tumor cell drug resistance by inverse regulation of hOCT3/SLC22A3 and ABC drug transporters in colon and kidney cancers. Cancer Letters 2019, 449, 237 -251.

AMA Style

Wing-Kee Lee, Frank Thévenod. Oncogenic PITX2 facilitates tumor cell drug resistance by inverse regulation of hOCT3/SLC22A3 and ABC drug transporters in colon and kidney cancers. Cancer Letters. 2019; 449 ():237-251.

Chicago/Turabian Style

Wing-Kee Lee; Frank Thévenod. 2019. "Oncogenic PITX2 facilitates tumor cell drug resistance by inverse regulation of hOCT3/SLC22A3 and ABC drug transporters in colon and kidney cancers." Cancer Letters 449, no. : 237-251.

Journal article
Published: 01 April 2019 in Journal of Biological Chemistry
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Receptor-mediated endocytosis is responsible for reabsorption of transferrin (Tf) in renal proximal tubules (PTs). Although the role of the megalin–cubilin receptor complex (MCRC) in this process is unequivocal, modalities independent of this complex are evident but as yet undefined. Here, using immunostaining and Tf-flux assays, FACS analysis, and fluorescence imaging, we report localization of Tf receptor 1 (TfR1), the cognate Tf receptor mediating cellular holo-Tf (hTf) acquisition, to the apical brush border of the PT, with expression gradually declining along the PT in mouse and rat kidneys. In functional studies, hTf uptake across the apical membrane of cultured PT epithelial cell (PTEC) monolayers increased in response to decreased cellular iron after desferrioxamine (DFO) treatment. We also found that apical hTf uptake under basal conditions is receptor-associated protein (RAP)-sensitive and therefore mediated by the MCRC but becomes RAP-insensitive under DFO treatment, with concomitantly decreased megalin and cubilin expression levels and increased TfR1 expression. Thus, as well as the MCRC, TfR1 mediates hTf uptake across the PT apical brush border, but in conditions of decreased cellular iron, hTf uptake is predominated by augmented apical TfR1. In conclusion, both the MCRC and TfR1 mediate hTf uptake across apical brush border membranes of PTECs and reciprocally respond to decreased cellular iron. Our findings have implications for renal health, whole-body iron homeostasis, and pathologies arising from disrupted iron balance.

ACS Style

Craig P. Smith; Wing-Kee Lee; Matthew Haley; Søren Brandt Poulsen; Frank Thévenod; Robert A. Fenton. Proximal tubule transferrin uptake is modulated by cellular iron and mediated by apical membrane megalin–cubilin complex and transferrin receptor 1. Journal of Biological Chemistry 2019, 294, 7025 -7036.

AMA Style

Craig P. Smith, Wing-Kee Lee, Matthew Haley, Søren Brandt Poulsen, Frank Thévenod, Robert A. Fenton. Proximal tubule transferrin uptake is modulated by cellular iron and mediated by apical membrane megalin–cubilin complex and transferrin receptor 1. Journal of Biological Chemistry. 2019; 294 (17):7025-7036.

Chicago/Turabian Style

Craig P. Smith; Wing-Kee Lee; Matthew Haley; Søren Brandt Poulsen; Frank Thévenod; Robert A. Fenton. 2019. "Proximal tubule transferrin uptake is modulated by cellular iron and mediated by apical membrane megalin–cubilin complex and transferrin receptor 1." Journal of Biological Chemistry 294, no. 17: 7025-7036.

Article
Published: 30 January 2019 in Biometals
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Cadmium (Cd2+) is a toxic and non-essential divalent metal ion in eukaryotic cells. Cells can only be targeted by Cd2+ if it hijacks physiological high-affinity entry pathways, which transport essential divalent metal ions in a process termed “ionic and molecular mimicry”. Hence, “free” Cd2+ ions and Cd2+ complexed with small organic molecules are transported across cellular membranes via ion channels, carriers and ATP hydrolyzing pumps, whereas receptor-mediated endocytosis (RME) internalizes Cd2+-protein complexes. Only Cd2+ transport pathways validated by stringent methodology, namely electrophysiology, 109Cd2+ tracer studies, inductively coupled plasma mass spectrometry, atomic absorption spectroscopy, Cd2+-sensitive fluorescent dyes, or specific ligand binding and internalization assays for RME are reviewed whereas indirect correlative studies are excluded. At toxicologically relevant concentrations in the submicromolar range, Cd2+ permeates voltage-dependent Ca2+ channels (“T-type” CaV3.1, CatSper), transient receptor potential (TRP) channels (TRPA1, TRPV5/6, TRPML1), solute carriers (SLCs) (DMT1/SLC11A2, ZIP8/SLC39A8, ZIP14/SLC39A14), amino acid/cystine transporters (SLC7A9/SLC3A1, SLC7A9/SLC7A13), and Cd2+-protein complexes are endocytosed by the lipocalin-2/NGAL receptor SLC22A17. Cd2+ transport via the mitochondrial Ca2+ uniporter, ATPases ABCC1/2/5 and transferrin receptor 1 is likely but requires further evidence. Cd2+ flux occurs through the influx carrier OCT2/SLC22A2, efflux MATE proteins SLC47A1/A2, the efflux ATPase ABCB1, and RME of Cd2+-metallothionein by the receptor megalin (low density lipoprotein receptor-related protein 2, LRP2):cubilin albeit at high concentrations thus questioning their relevance in Cd2+ loading. Which Cd2+-protein complexes are internalized by megalin:cubilin in vivo still needs to be determined. A stringent conservative and reductionist approach is mandatory to verify relevance of transport pathways for Cd2+ toxicity and to overcome dissemination of unsubstantiated conjectures.

ACS Style

Frank Thévenod; Johannes Fels; Wing-Kee Lee; Ralf Zarbock. Channels, transporters and receptors for cadmium and cadmium complexes in eukaryotic cells: myths and facts. Biometals 2019, 32, 469 -489.

AMA Style

Frank Thévenod, Johannes Fels, Wing-Kee Lee, Ralf Zarbock. Channels, transporters and receptors for cadmium and cadmium complexes in eukaryotic cells: myths and facts. Biometals. 2019; 32 (3):469-489.

Chicago/Turabian Style

Frank Thévenod; Johannes Fels; Wing-Kee Lee; Ralf Zarbock. 2019. "Channels, transporters and receptors for cadmium and cadmium complexes in eukaryotic cells: myths and facts." Biometals 32, no. 3: 469-489.

Chapter
Published: 30 December 2018 in Cadmium Interaction with Animal Cells
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Cadmium (Cd2+) is a non-essential divalent metal ion without physiological function in animal cells. For toxicity to occur, Cd2+ must first enter cells by utilizing physiological transport pathways for essential divalent metal ions, such as Fe2+, Zn2+, Cu2+, Ca2+, or Mn2+. ‘Free’ Cd2+ ions and Cd2+ ions bound to small organic molecules are transported via ion channels, carrier proteins or ATP hydrolyzing pumps, whereas metalloproteins are internalized by receptor-mediated endocytosis (RME). This review describes Cd2+ transport (influx/efflux) pathways that were validated by electrophysiology (e.g. patch clamp), 109Cd2+ flux, inductively coupled plasma mass spectrometry, atomic absorption spectroscopy, Cd2+-sensitive fluorescent dyes, specific ligand binding, and ligand internalization assays that are ideally studied in heterologous expression systems. Convincing evidence has been obtained for Cd2+ permeation for Ca2+ channels at toxicologically relevant concentrations (CaV3.1, CatSper) TRP channels (TRPA1, TRPV5/6, TRPML1), solute carriers (DMT1, ZIP8, ZIP14, system (b0, + AT)) and RME of Cd2+-protein complexes (Lipocalin-2 receptor). The carrier OCT2 mediates Cd2+ influx and MATE1/2 and the ATPase ABCB1 Cd2+ efflux at high, toxicologically irrelevant Cd2+ concentrations. L- and N-type voltage-, ligand-gated, store-operated Ca2+ channels, CFTR, connexins and the transporter ferroportin-1 are not permeated by Cd2+. More experimental evidence is needed for the mitochondrial Ca2+ uniporter, the ATPase ABCC1 and the transferrin receptor 1. Although the receptor megalin: cubilin mediates RME of Cd2+-metallothionein complex at high, but toxicologically irrelevant concentrations, its in vivo Cd2+-protein–ligand complexes still need to be identified. A stringent methodology is mandatory to prove additional Cd2+ transport pathways instead of propagating unsubstantiated speculations.

ACS Style

Frank Thévenod. Membrane Transport Proteins and Receptors for Cadmium and Cadmium Complexes. Cadmium Interaction with Animal Cells 2018, 1 -22.

AMA Style

Frank Thévenod. Membrane Transport Proteins and Receptors for Cadmium and Cadmium Complexes. Cadmium Interaction with Animal Cells. 2018; ():1-22.

Chicago/Turabian Style

Frank Thévenod. 2018. "Membrane Transport Proteins and Receptors for Cadmium and Cadmium Complexes." Cadmium Interaction with Animal Cells , no. : 1-22.

Journal article
Published: 07 November 2018 in Cell Communication and Signaling
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We have previously evidenced apical expression of the 24p3/NGAL/lipocalin-2 receptor (Lcn2-R; SLC22A17) in inner medullary collecting duct (IMCD) cells, which are present in vivo in a hyperosmotic/-tonic environment that activates canonical Wnt/β-catenin signaling. The localization of Lcn2-R in the inner medulla is intriguing considering local bacterial infections trigger toll-like receptor-4 (TLR-4)-mediated secretion of the bacteriostatic Fe3+-free (apo-)Lcn2. To determine the effects of osmolarity/tonicity changes, Wnt/β-catenin and TLR-4 activation on Lcn2-R and Lcn2 expression and cell viability in rat primary IMCD and mouse (m)IMCD3 cells. Normosmolarity/-tonicity was 300 mosmol/l whereas hyperosmolarity/-tonicity was induced by adding 100 mmol/l NaCl + 100 mmol/l urea (600 mosmol/l, 1-7 days). Lcn2-R and Lcn2 expression were determined by qPCR, immunoblotting, flow cytometry and immunofluorescence microscopy. β-catenin was silenced by RNAi. Cell viability/death was determined with MTT and LDH release assays. TLR-4 was activated by bacterial lipopolysaccharides (LPS). Hyperosmotic/-tonic media upregulated Lcn2-R by ~4-fold and decreased Lcn2 expression/secretion, along with Wnt/β-catenin activation, in IMCD cells. These effects of hyperosmotic/-tonic media on Lcn2-R/Lcn2 expression were reverted by normosmolarity/-tonicity, β-catenin silencing and/or LPS. Exposure of cells with endogenous or stably overexpressing Lcn2-R to apo-Lcn2 or LPS decreased cell viability. Lcn2-R upregulation and Lcn2 downregulation via Wnt/β-catenin may promote adaptive osmotolerant survival of IMCD cells in response to hyperosmolarity/-tonicity whereas Lcn2 upregulation and Lcn2-R downregulation via TLR-4 and/or normosmolarity/-tonicity may protect IMCD cells against bacterial infections and prevent autocrine death induction by Lcn2.

ACS Style

R. Betten; B. Scharner; S. Probst; B. Edemir; N. A. Wolff; C. Langelueddecke; W.-K. Lee; F. Thévenod. Tonicity inversely modulates lipocalin-2 (Lcn2/24p3/NGAL) receptor (SLC22A17) and Lcn2 expression via Wnt/β-catenin signaling in renal inner medullary collecting duct cells: implications for cell fate and bacterial infection. Cell Communication and Signaling 2018, 16, 1 -20.

AMA Style

R. Betten, B. Scharner, S. Probst, B. Edemir, N. A. Wolff, C. Langelueddecke, W.-K. Lee, F. Thévenod. Tonicity inversely modulates lipocalin-2 (Lcn2/24p3/NGAL) receptor (SLC22A17) and Lcn2 expression via Wnt/β-catenin signaling in renal inner medullary collecting duct cells: implications for cell fate and bacterial infection. Cell Communication and Signaling. 2018; 16 (1):1-20.

Chicago/Turabian Style

R. Betten; B. Scharner; S. Probst; B. Edemir; N. A. Wolff; C. Langelueddecke; W.-K. Lee; F. Thévenod. 2018. "Tonicity inversely modulates lipocalin-2 (Lcn2/24p3/NGAL) receptor (SLC22A17) and Lcn2 expression via Wnt/β-catenin signaling in renal inner medullary collecting duct cells: implications for cell fate and bacterial infection." Cell Communication and Signaling 16, no. 1: 1-20.

Journal article
Published: 03 September 2018 in Toxics
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During embryonic development, some hypoxia occurs due to incipient vascularization. Under hypoxic conditions, gene expression is mainly controlled by hypoxia-inducible factor 1 (HIF-1). The activity of this transcription factor can be altered by the exposure to a variety of compounds; among them is cadmium (Cd), a nephrotoxic heavy metal capable of crossing the placenta and reaching fetal kidneys. The goal of the study was to determine Cd effects on HIF-1 on embryonic kidneys. Pregnant Wistar rats were exposed to a mist of isotonic saline solution or CdCl2 (DDel = 1.48 mg Cd/kg/day), from gestational day (GD) 8 to 20. Embryonic kidneys were obtained on GD 21 for RNA and protein extraction. Results show that Cd exposure had no effect on HIF-1α and prolyl hydroxylase 2 protein levels, but it reduced HIF-1 DNA-binding ability, which was confirmed by a decrease in vascular endothelial growth factor (VEGF) mRNA levels. In contrast, the protein levels of VEGF were not changed, which suggests the activation of additional regulatory mechanisms of VEGF protein expression to ensure proper kidney development. In conclusion, Cd exposure decreases HIF-1-binding activity, posing a risk on renal fetal development.

ACS Style

Tania Jacobo-Estrada; Mariana Cardenas-Gonzalez; Mitzi Paola Santoyo-Sánchez; Frank Thevenod; Olivier Barbier. Intrauterine Exposure to Cadmium Reduces HIF-1 DNA-Binding Ability in Rat Fetal Kidneys. Toxics 2018, 6, 53 .

AMA Style

Tania Jacobo-Estrada, Mariana Cardenas-Gonzalez, Mitzi Paola Santoyo-Sánchez, Frank Thevenod, Olivier Barbier. Intrauterine Exposure to Cadmium Reduces HIF-1 DNA-Binding Ability in Rat Fetal Kidneys. Toxics. 2018; 6 (3):53.

Chicago/Turabian Style

Tania Jacobo-Estrada; Mariana Cardenas-Gonzalez; Mitzi Paola Santoyo-Sánchez; Frank Thevenod; Olivier Barbier. 2018. "Intrauterine Exposure to Cadmium Reduces HIF-1 DNA-Binding Ability in Rat Fetal Kidneys." Toxics 6, no. 3: 53.

Journal article
Published: 09 January 2018 in Scientific Reports
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Much of iron and manganese metabolism occurs in mitochondria. Uptake of redox-active iron must be tightly controlled, but little is known about how metal ions enter mitochondria. Recently, we established that the divalent metal transporter 1 (DMT1) is present in the outer mitochondrial membrane (OMM). Therefore we asked if it mediates Fe2+ and Mn2+ influx. Mitochondria were isolated from HEK293 cells permanently transfected with inducible rat DMT1 isoform 1 A/+IRE (HEK293-rDMT1). Fe2+-induced quenching of the dye PhenGreen™SK (PGSK) occurred in two phases, one of which reflected OMM DMT1 with stronger Fe2+ uptake after DMT1 overexpression. DMT1-specific quenching showed an apparent affinity of ~1.5 µM for Fe2+and was blocked by the DMT1 inhibitor CISMBI. Fe2+ influx reflected an imposed proton gradient, a response that was also observed in purified rat kidney cortex (rKC) mitochondria. Non-heme Fe accumulation assayed by ICPOES and stable 57Fe isotope incorporation by ICPMS were increased in HEK293-rDMT1 mitochondria. HEK293-rDMT1 mitochondria displayed higher 59Fe2+ and 54Mn2+ uptake relative to controls with 54Mn2+ uptake blocked by the DMT1 inhibitor XEN602. Such transport was defective in rKC mitochondria with the Belgrade (G185R) mutation. Thus, these results support a role for DMT1 in mitochondrial Fe2+ and Mn2+ acquisition.

ACS Style

Natascha A. Wolff; Michael Garrick; Lin Zhao; Laura M. Garrick; Andrew J. Ghio; Frank Thévenod. A role for divalent metal transporter (DMT1) in mitochondrial uptake of iron and manganese. Scientific Reports 2018, 8, 1 -12.

AMA Style

Natascha A. Wolff, Michael Garrick, Lin Zhao, Laura M. Garrick, Andrew J. Ghio, Frank Thévenod. A role for divalent metal transporter (DMT1) in mitochondrial uptake of iron and manganese. Scientific Reports. 2018; 8 (1):1-12.

Chicago/Turabian Style

Natascha A. Wolff; Michael Garrick; Lin Zhao; Laura M. Garrick; Andrew J. Ghio; Frank Thévenod. 2018. "A role for divalent metal transporter (DMT1) in mitochondrial uptake of iron and manganese." Scientific Reports 8, no. 1: 1-12.

Review
Published: 22 July 2017 in International Journal of Molecular Sciences
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Even decades after the discovery of Cadmium (Cd) toxicity, research on this heavy metal is still a hot topic in scientific literature: as we wrote this review, more than 1440 scientific articles had been published and listed by the PubMed.gov website during 2017. Cadmium is one of the most common and harmful heavy metals present in our environment. Since pregnancy is a very particular physiological condition that could impact and modify essential pathways involved in the handling of Cd, the prenatal life is a critical stage for exposure to this non-essential element. To give the reader an overview of the possible mechanisms involved in the multiple organ toxic effects in fetuses after the exposure to Cd during pregnancy, we decided to compile some of the most relevant experimental studies performed in experimental models and to summarize the advances in this field such as the Cd distribution and the factors that could alter it (diet, binding-proteins and membrane transporters), the Cd-induced toxicity in dams (preeclampsia, fertility, kidney injury, alteration in essential element homeostasis and bone mineralization), in placenta and in fetus (teratogenicity, central nervous system, liver and kidney).

ACS Style

Tania Jacobo-Estrada; Mitzi Santoyo-Sánchez; Frank Thévenod; Olivier Barbier. Cadmium Handling, Toxicity and Molecular Targets Involved during Pregnancy: Lessons from Experimental Models. International Journal of Molecular Sciences 2017, 18, 1590 .

AMA Style

Tania Jacobo-Estrada, Mitzi Santoyo-Sánchez, Frank Thévenod, Olivier Barbier. Cadmium Handling, Toxicity and Molecular Targets Involved during Pregnancy: Lessons from Experimental Models. International Journal of Molecular Sciences. 2017; 18 (7):1590.

Chicago/Turabian Style

Tania Jacobo-Estrada; Mitzi Santoyo-Sánchez; Frank Thévenod; Olivier Barbier. 2017. "Cadmium Handling, Toxicity and Molecular Targets Involved during Pregnancy: Lessons from Experimental Models." International Journal of Molecular Sciences 18, no. 7: 1590.

Book chapter
Published: 20 June 2017 in Encyclopedia of Cancer
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Frank Thévenod. Lipocalin. Encyclopedia of Cancer 2017, 2514 -2517.

AMA Style

Frank Thévenod. Lipocalin. Encyclopedia of Cancer. 2017; ():2514-2517.

Chicago/Turabian Style

Frank Thévenod. 2017. "Lipocalin." Encyclopedia of Cancer , no. : 2514-2517.

Journal article
Published: 20 March 2017 in Archives of Toxicology
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The renal proximal tubule (PT) is the major target of cadmium (Cd2+) toxicity where Cd2+ causes stress and apoptosis. Autophagy is induced by cell stress, e.g., endoplasmic reticulum (ER) stress, and may contribute to cell survival or death. The role of autophagy in Cd2+-induced nephrotoxicity remains unsettled due to contradictory results and lack of evidence for autophagic machinery damage by Cd2+. Cd2+-induced autophagy in rat kidney PT cell line NRK-52E and its role in cell death was investigated. Increased LC3-II and decreased p62 as autophagy markers indicate rapid induction of autophagic flux by Cd2+ (5-10 µM) after 1 h, accompanied by ER stress (increased p-PERK, p-eIF2α, CHOP). Cd2+ exposure exceeding 3 h results in p62/LC3-II accumulation, but diminished effect of lysosomal inhibitors (bafilomycin A1, pepstatin A +E-64d) on p62/LC3-II levels, indicating decreased autophagic flux and cargo degradation. At 24 h exposure, Cd2+ (5-25 µM) activates intrinsic apoptotic pathways (Bax/Bcl-2, PARP-1), which is not evident earlier (≤6 h) although cell viability by MTT assay is decreased. Autophagy inducer rapamycin (100 nM) does not overcome autophagy inhibition or Cd2+-induced cell viability loss. The autophagosome-lysosome fusion inhibitor liensinine (5 μM) increases CHOP and Bax/Bcl-2-dependent apoptosis by low Cd2+ stress, but not by high Cd2+. Lysosomal instability by Cd2+ (5 μM; 6 h) is indicated by increases in cellular sphingomyelin and membrane fluidity and decreases in cathepsins and LAMP1. The data suggest dual and temporal impact of Cd2+ on autophagy: Low Cd2+ stress rapidly activates autophagy counteracting damage but Cd2+ stress accrual disrupts autophagic flux and lysosomal stability, possibly resulting in lysosomal cell death.

ACS Style

W.-K. Lee; S. Probst; Mitzi Paola Santoyo-Sanchez; W. Al-Hamdani; I. Diebels; J.-K. Von Sivers; Evan Kerek; E. J. Prenner; F. Thévenod. Initial autophagic protection switches to disruption of autophagic flux by lysosomal instability during cadmium stress accrual in renal NRK-52E cells. Archives of Toxicology 2017, 91, 3225 -3245.

AMA Style

W.-K. Lee, S. Probst, Mitzi Paola Santoyo-Sanchez, W. Al-Hamdani, I. Diebels, J.-K. Von Sivers, Evan Kerek, E. J. Prenner, F. Thévenod. Initial autophagic protection switches to disruption of autophagic flux by lysosomal instability during cadmium stress accrual in renal NRK-52E cells. Archives of Toxicology. 2017; 91 (10):3225-3245.

Chicago/Turabian Style

W.-K. Lee; S. Probst; Mitzi Paola Santoyo-Sanchez; W. Al-Hamdani; I. Diebels; J.-K. Von Sivers; Evan Kerek; E. J. Prenner; F. Thévenod. 2017. "Initial autophagic protection switches to disruption of autophagic flux by lysosomal instability during cadmium stress accrual in renal NRK-52E cells." Archives of Toxicology 91, no. 10: 3225-3245.

Journals
Published: 01 January 2016 in Metallomics
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A review of iron and cadmium transport by renal tubules highlighting common pathways and differences with their implications for health and disease.

ACS Style

Frank Thévenod; Natascha A. Wolff. Iron transport in the kidney: implications for physiology and cadmium nephrotoxicity. Metallomics 2016, 8, 17 -42.

AMA Style

Frank Thévenod, Natascha A. Wolff. Iron transport in the kidney: implications for physiology and cadmium nephrotoxicity. Metallomics. 2016; 8 (1):17-42.

Chicago/Turabian Style

Frank Thévenod; Natascha A. Wolff. 2016. "Iron transport in the kidney: implications for physiology and cadmium nephrotoxicity." Metallomics 8, no. 1: 17-42.