Increased, Accumulation of alpha2u microglobulin (proximal tubular epithelium)

7440-43-9

BDOSMKKIYDKNTQ-UHFFFAOYSA-N

Cadmium

Cadimium CADMIUM BLUE CADMIUM, IN PLATTEN, STANGEN, BROCKEN,KOERNER

DTXSID1023940

7439-97-6

QSHDDOUJBYECFT-UHFFFAOYSA-N

Mercury

Liquid silver Mercure MERCURIC METAL TRIPLE DISTILLED mercurio Mercury element Quecksilber Quicksilver UN 2024 UN 2809

DTXSID1024172

7440-61-1

JFALSRSLKYAFGM-UHFFFAOYSA-N

Uranium

Uranium, isotope of mass 238 238U Element UN 2979 (DOT) Uranium I

DTXSID1042522

7440-22-4

BQCADISMDOOEFD-UHFFFAOYSA-N

Silver

Ag Nanopaste NPS-J 90 Ag Sphere 2 Ag-C-GS Algaedyn Arctic Silver 3 Argentum Astroflake 5 Carey Lea silver Colloidal silver Dotite XA 208 Du Pont 4943 ECM 100AF4810 Enlight 600 Enlight silver plate 600 Epinall Finesphere SVND 102 Fordel DC FP 5369-502 Jelcon SH 1 Jungindai Takasago 300 KS (metal) LCP 1-19SFS Metz 3000-1 Nanomelt AGC-A Nanomelt Ag-XA 301 Nanomelt Ag-XF 301 Nanomelt Ag-XF 301H Nanopaste NPS-J 90 Perfect Silver Puff Silver X 1200 RT 1710S-C1 SD (metal) Shell Silver Silbest E 20 Silbest F 20 Silbest J 18 Silbest TC 12 Silbest TC 20E Silbest TC 25A Silbest TCG 1 Silbest TCG 7 Silcoat AgC 103 Silcoat AgC 2011 Silcoat AgC 209 Silcoat AgC 2190 Silcoat AgC 222 Silcoat AgC 2411 Silcoat AgC 74T Silcoat AgC-A Silcoat AgC-AO Silcoat AgC-B Silcoat AgC-BO Silcoat AgC-D Silcoat AgC-G Silcoat AgC-GS Silcoat AgC-L Silcoat AgC-O Silcoat GS Silcoat RF 200 Silflake 135 Silsphere 514 Silver atom Silver element Silver Flake 1 Silver Flake 25 Silver Flake 52 Silver Flake 7A SILVER FLAKES Silver metal Silvest TCG 11N Technic 299 Technic 450 Techno Alpha 175

DTXSID4024305

7440-38-2

RQNWIZPPADIBDY-UHFFFAOYSA-N

Arsenic

As Arsenic black ARSENIC METAL arsenico Grey arsenic UN 1558

DTXSID4023886

7440-57-5

PCHJSUWPFVWCPO-UHFFFAOYSA-N

Gold

AGC Micro Britecote Burnish Gold C.I. Pigment Metal 3 Colloidal gold Finesphere Gold W 011 Furuuchi 8560 Gold black Gold element Gold Flake Gold Leaf Keradec Palegold 5550 Perfect Gold Shell Gold Technic 504

DTXSID3064697

15663-27-1

DQLATGHUWYMOKM-UHFFFAOYSA-L

Cisplatin

Cis Platinum, diamminedichloro-, (SP-4-2)- Abiplatin Biocisplatinum Briplatin cis-DDP cis-Diaminedichloroplatinum cis-Diaminedichloroplatinum(II) cis-Diaminodichloroplatinum(II) cis-Diamminedichloroplatinum cis-Diamminedichloroplatinum(II) cis-Dichlorodiamineplatinum(II) cis-Dichlorodiammineplatinum cis-Dichlorodiammineplatinum(II) Cismaplat cis-Platin cisplatine cis-Platine cisplatino cis-Platinous diaminodichloride Cisplatinum cis-Platinum cis-Platinum diaminodichloride cis-Platinum II cis-Platinum(II) diaminodichloride cis-Platinum(II) diamminedichloride cis-Platinumdiamine dichloride cis-Platinumdiammine dichloride Cisplatyl Citoplatino Lederplatin lipoplatin Neoplatin NSC 119875 Platamine Platiblastin Platidiam Platinex Platinol Platinol AQ Platinoxan Platinum, diamminedichloro-, cis- Platistin Platosin SPI 077B103 cis-Dichlorodiamine platinum cis-Dichloro diaminoplatinum II

DTXSID4024983

5989-27-5

XMGQYMWWDOXHJM-JTQLQIEISA-N

D-Limonene

(4R)-1-Methyl-4-(prop-1-en-2-yl)cyclohexene Cyclohexene, 1-methyl-4-(1-methylethenyl)-, (4R)- (+)-(4R)-Limonene (+)-(R)-Limonene (+)-Dipentene (+)-Limonene (+)-p-Mentha-1,8-diene (+)-α-Limonene (4R)-(+)-Limonene (4R)-1-Methyl-4-(1-methylethenyl)cyclohexene (4R)-Limonene (R)-(+)-LIMONENE (R)-(+)-p-Mentha-1,8-diene (R)-1-Methyl-4-(1-methylethenyl)cyclohexene (R)-1-METHYL-4-ISOPROPENYL-1-CYCLOHEXENE (R)-4-Isopropenyl-1-methyl-1-cyclohexene (R)-Limonene (R)-p-menta-1,8-dieno (R)-p-Mentha-1,8-dien (R)-p-mentha-1,8-diene Biogenic SE 374 Carvene CYCLOHEXANE, 1-METHYL-4-(1-METHYLETHENYL)-, Cyclohexene, 1-methyl-4-(1-methylethenyl)-, (R)- CYCLOHEXENE, 1-METHYL-4-(1-METHYLETHENYL)-, d-(+)-Limonene D-LIMONEN Glidesafe Glidsafe LIMONENE PURE Limonene, (+)- LIMONENE, (R)-(+)- p-Mentha-1,8-diene, (R)-(+)- Refchole TERPENE HYDROCARBONS

DTXSID1020778

PR:P02761

PR major urinary protein (rat)

CL:1000507

CL kidney tubule cell

D000236

MESH Adenoma

D002277

MESH Carcinoma

GO:0008219

GO cell death

GO:0050673

GO epithelial cell proliferation

D002292

MESH Carcinoma, Renal Cell

D006965

MESH hyperplasia

GO:0005488

GO binding

WIKI increased

Cadmium

2017-10-25T08:33:12

Mercury

2016-11-29T18:42:19

Uranium

2021-08-05T14:28:50

Silver

2022-02-03T11:20:11

Arsenic

2021-04-27T00:15:21

Gold

2022-02-07T15:25:56

Nanoparticles and Micrometer Particles

2022-02-04T13:43:43

Cisplatin

2022-02-03T11:34:57

D-limonene

2016-11-29T18:42:27

Hydrocarbons, various

2016-11-29T18:42:27

10116

NCBI Rattus norvegicus

Increased, Accumulation of alpha2u microglobulin (proximal tubular epithelium)

Tissue

UBERON:0008404

UBERON proximal tubular epithelium

AOPWiki 2016-11-29T18:41:26

2017-09-16T10:16:01

Increase, Cytotoxicity (renal tubular cell)

Cellular

The renal proximal tubule is a crucial section of the nephron, responsible for the bulk of its reabsorption capabilities. About 60-70% of glomerular filtrate such as water, small molecules, and important ions, as well as nearly all the filtered amino acids, small peptides, and glucose are reabsorbed in the proximal tubule (Carson, 2019). The process of solute reabsorption is highly energetically expensive, making the proximal tubules the renal region of highest oxygen consumption. The microvilli, densely packed to form the brush border apical surface of the tubules, have abundant elongated mitochondria to sustain the energetic demand of their function (Carlson, 2019). The introduction of heavy metals into the kidneys causes aggregation in the proximal tubules due to their high mitochondrial content, leading to inhibition of the electron transport chain and reactive oxygen species (ROS) production. This area is particularly susceptible to heavy metal toxicity due to the abundance of mitochondria, as well as the fact that, regardless of toxicity, approximately 70% of cation absorption and transport passes through the proximal tubules (Barbier et al., 2005). Some heavy metal transport into the proximal tubules is conducted by MRP-1 and MRP-2 (ATP binding cassette-multidrug resistance proteins), and characterize toxicity by GSH depletion as some metals such as arsenic bind GSH and increased oxidative stress induced by free radicals (Sabath & Robles-Osorio, 2012). This oxidative stress causes disruption to mitochondrial homeostasis and mitophagy in proximal tubular epithelial cells by altering PPAR (peroxisome proliferator-activated receptor) (Small et al., 2018). At high enough concentrations of toxic heavy metals they can lead to cytotoxicity and cell death. An issue with assessment of kidney function is that the kidneys notoriously compensate for loss of function, leading to the appearance of adverse affects only at a late onset when there is very severe levels of damage (de Burbure et al., 2003). Cell Death and Cytotoxicity Cell death is a variety of processes defined by a cell ceasing to perform its function. This could happen by a variety of mechanisms. Apoptosis is a programmed physiological sequence leading to controlled cell death deemed necessary for the fitness and survival of the organism (cell is redundant, dysfunctional, cancerous, etc.) (Choi et al., 2019). Apoptosis, in the case of DNA damage, can be induced by free radicals produced as a result of heavy metal exposure, as shown in ex-vivo studies (Miller et al., 2002). Another cause by heavy metal exposure is physical and structural damage to mitochondria, damaging cellular metabolism and ATP production. There are many possible stressors that may lead to cell death, the effects exhibited depend on the cell type and the severity of the stress (Liu et al., 2018). Some modes of cell death include: apoptosis (programmed cell death), necrosis (uncontrolled cell death), and aging-caused cell death, known as senescent death  (Liu et al., 2018). <div>Apoptosis, also referred to as programmed cell death, is the predetermined procedure by which an organism disposes of cells that are no longer productive (Liu et al., 2018; Elmore, 2007). Apoptosis biochemically  manifests as cytoplasmic shrinkage, cytoskeleton collapse, chromatin condensation (pyknosis), nuclear fragmentation (karyorrhexis), mitochondrial dysfunction, cytochrome c release, altered Bcl-2 family protein expression or activation, plasma membrane blebbing, and in larger cells, the formation of apoptotic bodies. The surface of cells undergoing apoptosis is chemically altered to signal nearby cells and macrophages that then rapidly engulf them before they spill their contents (Alberts et al., 2014; Choi et al., 2019). Apoptosis occurs in three general phases: initiation, effector, and final. Variation can be seen as the initiation phase is dependant on stimuli, and there are two effector phase modes; an extrinsic and intrinsic pathways. Regardless of the pathway of the first 2 phases, the final stage of apoptosis is caspase-3 activation (Priant et al., 2019). The initiation and execution of apoptosis and other cell death processes is induced by the proteolytic activity of caspase as it cleaves the aspartic acid residues of proteins. The caspases can be broadly divided into two groups: those that are mainly involved in apoptosis (caspase-2, -3, -6, -7, -8, -9, and -10) and those related to caspase-1, whose primary role appears to be cytokine processing and pro-inflammatory cell death (caspase-1, -4, -5, -11, -12, -13, and -14). The apoptotic caspases can further be divided into initiator caspases (caspase-2, -8, -9, and -10) and executioner caspases (caspase-3, -6, and-7) (Fink & Cookson, 2005). Once the initial caspase activation occurs the resultant caspase cascade is irreversible (Alberts et al., 2014).</div> <div> </div> The extrinsic pathway, also known as the death receptor-mediated pathway, involves the ligation of death receptors determining the activation of caspase-8. Caspase-8 further activates downstream caspases leading to apoptosis (Priante et al., 2019). This pathway is triggered by extracellular signalling proteins binding to cell-surface death receptors. A well understood example of this process is the activation of the Fas receptor on the surface of a target cell by Fas ligand (FasL) on the surface of a cytotoxic lymphocyte (Alberts et al., 2014). In this process, the cytosolic Fas death receptor binds intracellular adaptor proteins. This complex then binds initiator, caspases, primarily caspase-8, forming a death-inducing signalling complex (DISC). The initiator caspases, once dimerized and activated in the DISC, activate downstream executioner caspases to induce apoptosis (Nair et al., 2014). In some cells, the extrinsic pathway recruits the intrinsic apoptotic pathway to amplify the caspase cascade. These pathways are linked by caspase-8, that triggers the caspase cascade and the protein, Bid (Priante et al., 2019; Alberts et al., 2014). Type I cells act independent of mitochondria for the induction of Fas death receptor-mediated apoptosis, and have therefore optimized the extrinsic pathway. Thymocytes or cells responsible for the immune system in general, for example, are expected to signal each other or target cells through membrane bound ligands, like FasL and TRAIL (Ozoren and El-Deiry, 2002). The intrinsic pathway is often referred to as the mitochondrial pathway of apoptosis. Pro-apoptotic Bcl-2 family proteins, Bax and Bak, create pores on the outer mitochondrial membrane, determining the release of apoptogenic factors, such as cytochrome c. In the cytosol, cytochrome c binds to, and stimulates, conformational modifications in the adaptor protein, Apaf-1, thus leading to the enrolment and activation of caspase-9. Caspase-9 further activates executioner caspases to elicit apoptosis (Priante et al., 2019). Type II cells are mitochondria-dependent, where the mitochondria are crucial to ensure successful apoptosis. For example, liver and kidney cells are responsible for the detoxification of the blood from chemicals toxicants, many of which are cytotoxic and genotoxic agents known to predominantly activate the intrinsic pathway (Ozoren and El-Deiry, 2002). In a study conducted by Eichler et al. (2006), cultured murine podocytes were incubated for three days with arsenite, cadmiuim, or mercury, as well as an equimolar combination of the three to test the modes and extent of apoptosis induced by the exposure. It was seen that the mix of metal exposure showed significantly fewer apoptotic affects, indicating an antagonistic affect of the metals over an additive or synergistic toxicity. It was also seen that the apoptosis observed in the separate metal tests showed a ~400% increase of caspase 8 activity as well as ~500% upregulation of Fas, factors of the extrinsic pathway. No significant change was seen to the intrinsic pathway factors. The results of this experiment indicate that heavy metals favour extrinsic apoptosis as their method of cytotoxicity. Necrosis is characterized as passive, accidental cell death resulting from environmental perturbation with uncontrolled release of inflammatory cellular contents (Fink & Cookson, 2005). Contrastingly, apoptosis is an active, intentional, programmed process of autonomous cellular dismantling that avoids eliciting inflammation. These modes would then be categorized into Accidental Cell Death (ACD) and Regulated Cell Death (RCD), respectively fitting necrosis and apoptosis (Choi et al., 2019). Necrosis biochemically manifests through plasma membrane rupture, cell swelling and lysis, energy decline, DAMP release, and emptying of cell contents (Choi et al., 2019; Thiebault et al., 2007). The caspases governing inflammatory cell death, such as necrosis, are caspases-1, -4, -5, -11, -12, -13, and -14 (Fink and Cookson, 2005). Cell fate could be decided by a number of factors. For instance, ATP is required for the execution of apoptosis, so, when lacking, apoptosis is disabled, making the mode of cell death ATP dependent (Shaki et al., 2012). Between apoptosis and necroptosis, cell fate is influenced primarily by the availability of caspase-8 and the cellular or X-linked inhibitors of apoptosis proteins (cIAP1, cIAP2, XIAP). Thiebault et al. (2007) studied the mechanism of cell mortality induced by uranium in NRK-52E cells and found that after low exposure to uranium (below the CI50 concentration, 500µL), apoptotic cell death was observed, whereas higher exposure to uranium resulted in necrotic cell death. Multiple types of death can be observed simultaneously in tissues exposed to the same stimulus, and the local intensity of a particular stimulus may influence the cell death mechanism (Fink and Cookson, 2005).

<table border="1" cellpadding="1" cellspacing="1"> <tbody> <tr> <td>Assay Type & Measured Content</td> <td>Description</td> <td>Dose Range Studied</td> <td> Assay Characteristics (Length/Ease of use/Accuracy)</td> </tr> <tr> <td> Kidney function assay Measuring total urinary protein, albumin, transferrin, b2-microglobulin, retinolbinding protein, brush border tubular antigens, N-acetyl-b-Dglucosaminidase activity, serum and urinary creatine   (de Burbure et al., 2003)</td> <td>“All analyses of a given parameter were performed under similar experimental conditions in the same laboratories within 6mo of collection. Total urinary protein (Prot-T-U) was determined by the Coomassie blue G250 binding method. Albumin (Alb-U), transferrin (Transf-U), β2-microglobulin (β2m-U), and retinolbinding protein (RBP-U) in urine were quantified by latex immunoassay (Bernard & Lauwerys, 1983). Acceptable limits for precision and accuracy of measurements and external quality controls were the same as those described in the Cadmibel study (Lauwerys et al., 1990). The brush border tubular antigens (BBA-U) were analyzed by a sandwich enzyme-linked immunoassay using monoclonal antibodies (Mutti et al., 1985). The total activity of N-acetyl-β-Dglucosaminidase (NAG-T-U) in urine was determined colorimetrically using a kit (PPR Diagnostics Ltd.) as described elsewhere (Price et al., 1996). Only total NAG (NAG-T) was used for the purpose of this study. Serum and urinary creatinine (Creat-U) were measured by the methods of Heinegard and Tiderström (1973), and Jaffé, respectively (Henry, 1965).” (de Burbure et al., 2003)</td> <td>“The soil contamination in the area varied from 100 to 1700ppm lead (with values higher than 1000ppm in the immediate vicinity of the factories), 0.7 to 233ppm cadmium, and 101 to 22,257ppm zinc, with the highest concentrations being recorded within 500 m of the 2 factories”</td> <td> </td> </tr> <tr> <td> N-ACETYL-b-D-GLUCOSAMINIDASE (NAG) ASSAY Measuring NAG urinary content (Lim et al., 2016)</td> <td>“Urinary NAG activity was measured by using NAG Quantitative Kit (Shionogi, Osaka, Japan). After storing a synthetic substrate solution (1 mL) at 37°C for five minutes, the solution was mixed with the supernatant of the urine samples (50 mL) received after centrifugation. After storing it at 37°C for 15 min, stopping solution (2 mL) was added to and mixed with it. By using a spectrophotometer, its fluorescence intensities were measured with a wavelength of 580 nm (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780232/#b13-tr-32-057">13</a>,<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780232/#b14-tr-32-057">14</a>). Urinary β2-MG was measured by using Enzygnost β2-MG Micro Kit (Behring Institute, Mannheim, Germany). Its method used the principle of solid phase enzyme-linked immunosorbent assay (ELISA). Monoclonal anti-β2-MG antibody and anti-2-MG-horseradish peroxidase conjugate solution were used. After that, color intensities were measured with a wavelength of 450 nm by using a spectrophotometer (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780232/#b13-tr-32-057">13</a>,<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780232/#b14-tr-32-057">14</a>).” (Lim et al., 2016)</td> <td>Cd & Pb</td> <td>Fast, easy, accurate</td> </tr> <tr> <td> MTT Assay (cytotoxicity) Measuring Cell Viability (Thiebault et al., 2007; Shaki et al., 2012)</td> <td>This assay is a quantitative and sensitive method of detection of cell proliferation, measuring the growth rate of cells via activity and absorbance. It relies on the reduction of MTT (yellow, water-soluble tetrazolium dye) by mitochondrial dehydrogenases, to purple colored formazan crystals. The samples are then analyzed via spectrophotometry (550 nm). This assay can also be used to asses electron transport function.</td> <td> 50, 100 and 500 μM of uranyl acetate; 0-1000µM U</td> <td> Long Easy/Difficult High accuracy (mathematical measurement) Medium Precision</td> </tr> <tr> <td> LDH Cytotoxicity Assay Measuring Necrosis via Lactate Dehydrogenase release (Thiebault et al., 2007)</td> <td>LDH is released into extracellular space when the plasma membrane is damaged. To detect the leakage of LDH into cell culture medium as a measurement of membrane integrity, a tetrazolium salt is used in this assay. LDH oxidizes lactate to generate NADH, which then reacts with WST to generate a yellow colour. LDH activity can then be quantified by spectrophotometer or plate reader. </td> <td>15, 30 µM Cd</td> <td>Fast, easy, high accuracy</td> </tr> <tr> <td> Caspase-3 and -8 colorimetric assay, Caspase-9 fluoresceine assay Measuring apoptosis initiation and execution via caspases 3, 8, 9 activity (Thiebault et al., 2007)</td> <td>After cell lysate centrifugation, 10 µL of the supernatant was incubated with 80 µL of the caspase assay buffer and 10 µL of the colorimetric caspase-3 (Acetyl-asp-glu-val-asp-p-nitroanilide) or caspase-8 (Acetyl-ile-glu-thr-asp-p-nitroaniline) substrate. Plates were incubated for 90 min at 37° C and absorbance was read at 405 nm with a Statfax-2100 microplate reader. Fluorescence intensity of cell suspensions measuring caspase-9 activity was measured at an excitation wavelength of 490 nm and an emission wavelength of 530 nm with fluorescence spectrophotometer.</td> <td>0-800µM U</td> <td>Long, difficult, high accuracy</td> </tr> </tbody> </table> “Techniques such as micropuncture, microinjection [1, 6, 18] and microperfusion of isolated tubules [14] have made it possible to map the reabsorption of the heavy metals along the different segments of the nephron.” (Barbier et al., 2005) “Pb2+ , Hg2+ induced glomerular and tubular damage characterized by a reduced GFR, glycosuria, proteinuria and a rapid obstruction of the tubular system [13]” (Barbier et al., 2005) “Concerning chronic intoxication, most heavy metals (Cd2+ , Hg2+ , Pb2+ ) induced a Fanconi syndrome characterized by a decrease of the GFR, an increase in urinary flow rate, proteinuria, glycosuria, aminoaciduria and excessive loss of major ions.” (Barbier et al., 2005) “In the proximal tubule, Cd2+ has been shown to decrease phosphate and glucose transport by inhibiting the NaPi and the Na/glucose cotransporters respectively.” (Barbier et al., 2005) “In the kidney, Cd mainly affects PCT cells. This damage manifests clinically as low molecular weight proteinuria, aminoaciduria, bicarbonaturia, glycosuria and phosphaturia. Tubular damage markers such as alpha-1-microglobulin, beta-2-microglobulin, NAG and KIM-1 (kidney injury molecule-1) are useful in detecting early tubular damage.” (Sabath & Robles-Osorio, 2012)

All animals with kidneys containing renal proximal tubules.

CL:1000507

CL kidney tubule cell

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Extract from aronia melanocarpa L. berries protects against cadmium-induced lipid peroxidation and oxidative damage to proteins and DNA in the liver: A study using a rat model of environmental human exposure to this xenobiotic. Nutrients, 11, 758. doi:10.3390/nu11040758 Nair, P., Lu, M., Petersen, S., & Ashkenazi, A. (2014). Chapter five - apoptosis initiation through the cell-extrinsic pathway. Methods in Enzymology, 544, 99-128. doi:<a href="https://doi.org/10.1016/B978-0-12-417158-9.00005-4">https://doi.org/10.1016/B978-0-12-417158-9.00005-4</a> Ozoren, N., & El-Deiry, W. S. (2002). WS. Defining characteristics of types I and II apoptotic cells in response to TRAIL.4(6), 551-557. doi:10.1038/sj.neo.7900270 Pan, Y., Leifer, A., Ruau, D., Neuss, S., Bonrnemann, J., Schmid, G., . . . Jahnen-Dechent, W. (2009). Gold nanoparticles of diameter 1.4 nm trigger necrosis by oxidative stress and mitochondrial damage. Small, 5(8), 2067-2076. doi:10.1002/smll.200900466 Priante, G., Gianesello, L., Ceol, M., Del Prete, D., & Anglani, F. (2019). Cell death in the kidney. International Journal of Molecular Sciences, 20(14), 3598. doi: 10.3390/ijms20143598. doi:10.3390/ijms20143598 [doi] Rouas, C., Bensoussan, H., Suhard, D., Tessier, C., Grandcolas, L., Rebiere, F., . . . Gueguen, Y. (2010). Distribution of soluble uranium in the nuclear cell compartment at subtoxic concentrations. Chemical Research in Toxicology, 23(12), 1883-1889. doi:10.1021/tx100168c Sabath, E., & Robles-Osorio, M. L. (2012). Renal health and the environment: Heavy metal nephrotoxicity. Revista Nefrologia, doi:10.3265/Nefrologia.pre2012.Jan.10928 Santos, N. A. G., Catão, C. S., Martins, N. M., Curti, C., Bianchi, M. L. P., & Santos, A. C. (2007). Cisplatin-induced nephrotoxicity is associated with oxidative stress, redox state unbalance, impairment of energetic metabolism and apoptosis in rat kidney mitochondria. Archives of Toxicology, 81(7), 495-504. doi:10.1007/s00204-006-0173-2 Shaki, F., Hosseini, M. J., Ghazi-Khansari, M., & Pourahmad, J. (2012). Toxicity of depleted uranium on isolated rat kidney mitochondria. Biochimica Et Biophysica Acta - General Subjects, 1820(12), 1940-1950. doi:10.1016/j.bbagen.2012.08.015 Small, D. M., Sanchez, W. Y., Roy, S. F., Morais, C., Brooks, H. L., Coombes, J. S., . . . Gobe, G. (2018). N-acetyl-cysteine increases cellular dysfunction in progressive chronic kidney damage after acute kidney injury by dampening endogenousantioxidant responses. American Physiological Society - Renal Physiology, 314, F956-F968. doi:10.1152/ajprenal.00057.2017 Spreckelmeyer, S., Estrada-Ortiz, N., Prins, G. G. H., van der Zee, M., Gammelgaard, B., Sturup, S., . . . Casini, A. (2017). On the toxicity and transportation mechanisms of cisplatin in kidney tissues in comparison to a gold-based cytotoxic agent. Metallomics, 9, 1786. doi:10.1039/c7mt00271h Tad Eichler, Qing Ma, Caitlin Kelly, Jaya Mishra, Samir Parikh, Richard F. Ransom, Prasad Devarajan, William E. Smoyer, Single and Combination Toxic Metal Exposures Induce Apoptosis in Cultured Murine Podocytes Exclusively via the Extrinsic Caspase 8 Pathway, Toxicological Sciences, Volume 90, Issue 2, April 2006, Pages 392–399, <a href="https://doi.org/10.1093/toxsci/kfj106">https://doi.org/10.1093/toxsci/kfj106</a>Elmore, S. (2007). Apoptosis: A review of programmed cell death. Toxicologic Pathology, 35(4), 495-516. doi:779478428 [pii] Thiébault, C., Carrière, M., Milgram, S., Simon, A., Avoscan, L., & Gouget, B. (2007). Uranium induces apoptosis and is genotoxic to normal rat kidney (NRK-52E) proximal cells. Toxicological Sciences : An Official Journal of the Society of Toxicology, 98(2), 479-487. doi:kfm130 [pii] Turk, E., Kandemir, F. M., Yildirim, S., Caglayan, C., Kucukler, S., & Kuzu, M. (2019). Protective effect of hesperidin on sodium arsenite-induced nephrotoxicity and hepatotoxicity in rats. Biological Trace Element Research, 189, 95-108. doi:10.1007/s12011-018-1443-6 Yu, L., Li, W., Chu, J., Chen, C., Li, X., Tang, W., . . . Xiong, Z. (2021). Uranium inhibits mammalian mitochondrial cytochrome c oxidase and ATP synthase. Environmental Pollution, 271, 116377. doi:10.1016/j.envpol.2020.116377 Zhang, H., Chang, Z., Mehmood, K., Abbas, R. Z., Nabi, F., Rehman, M. U., . . . Zhou, D. (2018). Nano copper induces apoptosis in PK-15 cells via a mitochondria-mediated pathway. Biological Trace Element Research, 181(1), 62-70. doi:10.1007/s12011-017-1024-0   AOPWiki 2016-11-29T18:41:26

2022-03-03T15:14:42

Increase, Regenerative cell proliferation (tubular epithelial cells)

Cellular

CL:1000494

CL nephron tubule epithelial cell

AOPWiki 2016-11-29T18:41:26

2017-09-16T10:16:00

Increase, Adenomas/carcinomas (renal tubular)

Tissue

UBERON:0009773

UBERON renal tubule

AOPWiki 2016-11-29T18:41:26

2017-09-16T10:16:00

Increase, Hyperplasia (renal tubular cells)

Cellular

CL:1000507

CL kidney tubule cell

AOPWiki 2016-11-29T18:41:26

2017-09-16T10:16:01

Increased, Binding of chemicals to 2u (serum)

Molecular

UBERON:0001977

UBERON serum

AOPWiki 2016-11-29T18:41:26

2017-09-16T10:16:02

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42eb178c58> AOPWiki 2016-11-29T18:41:35

2016-12-03T16:37:59

<upstream-id>e775013c-617d-4a46-b268-f26262f6399a</upstream-id> <downstream-id>2580dd8c-7d47-4611-b344-268e72f499b8</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42eafecc40> AOPWiki 2016-11-29T18:41:35

2016-12-03T16:37:59

<upstream-id>2580dd8c-7d47-4611-b344-268e72f499b8</upstream-id> <downstream-id>9e4ab84f-e381-4855-9ace-7e772bbfc318</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00005eb8a025f398> AOPWiki 2016-11-29T18:41:35

2016-12-03T16:37:59

<upstream-id>9e4ab84f-e381-4855-9ace-7e772bbfc318</upstream-id> <downstream-id>5d0035ca-14c2-489f-8326-964293b6e217</downstream-id> Sustained regenerative proliferation directly leads to renal tubular hyperplasia.

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00005eb89f3896e8> AOPWiki 2016-11-29T18:41:35

2016-12-03T16:38:00

<upstream-id>5d0035ca-14c2-489f-8326-964293b6e217</upstream-id> <downstream-id>1b3d8ecc-f2d6-4a76-9f7e-a7b829073924</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00005eb8a0c1e730> AOPWiki 2016-11-29T18:41:35

2016-12-03T16:38:00

Alpha2u-microglobulin cytotoxicity leading to renal tubular adenomas and carcinomas (in male rat)

α2u-globulin- renal adenomas/carcinomas

Evgeniia Kazymova

Cancer AOP Workgroup. National Health and Environmental Effects Research Laboratory, Office of Research and Development, Integrated Systems Toxicology Division, US Environmental Protection Agency, Research Triangle Park, NC. Corresponding author for wiki entry (wood.charles@epa.gov)

BY-SA

1.29

1.0

This putative adverse outcome pathway (AOP) outlines potential key events leading to a tumor outcome in standard carcinogenicity models. This information is based largely on modes of action described previously in cited literature sources and is intended as a resource template for AOP development and data organization. Presentation in this Wiki does not indicate EPA acceptance of a particular pathway for a given reference agent, only that the information has been proposed in some manner. In addition, this putative AOP relates to the model species indicated and does not directly address issues of human relevance.

adjacent

Not Specified

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Not Specified Male Not Specified

<a href="#Life_Stage_Applicability">Life Stage Applicability</a>, <a href="#Taxonomic_Applicability"> Taxonomic Applicability</a>, <a href="#Sex_Applicability"> Sex Applicability</a> Elaborate on the domains of applicability listed in the summary section above. Specifically, provide the literature supporting, or excluding, certain domains. <ul> <li>Sex: This AOP applies to males only (Swenberg, 1993).</li> <li>Life stages: The relevant life stages for this AOP are reproductively mature adults. Alpha2u-microglobulin is found in the urine of female and sexually immature rats at concentrations that are less than 1/100 that found in young adult males (Vandoren et al 1983, Ekstrom et al 1984, as cited in Swenberg 1993). Hepatic synthesis accounts for most of the o2u in male rats, with synthesis beginning at the onset of sexual maturity and increasing to 20 weeks of age, after which it plateaus and then begins to decline with increasing age (Roy et al 1983, as cited in Swenberg 1993).</li> <li>Taxonomic: The taxonomic applicability domain of this AOP is rats, Rattus norvegicus (Swenberg, 1993).</li> </ul>

Swenberg, J. A. (1993). Alpha 2u-globulin nephropathy: review of the cellular and molecular mechanisms involved and their implications for human risk assessment. Environ Health Perspect, 101 Suppl 6, 39-44. AOPWiki 2016-11-29T18:41:16

2023-09-25T16:26:50