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Yogita Mehra, Pragasam Viswanathan. Early Evidence of Global DNA Methylation and Hydroxymethylation Changes in Rat Kidneys Consequent to Hyperoxaluria-Induced Renal Calcium Oxalate Stones. CYTOL GENET+ 2022; 56:458-465. [DOI: 10.3103/s0095452722050085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/27/2022] [Accepted: 08/30/2022] [Indexed: 11/30/2022]
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Magalhães EP, Silva BP, Aires NL, Ribeiro LR, Ali A, Cavalcanti MM, Nunes JVS, Sampaio TL, de Menezes RRPPB, Martins AMC. (-)-α-Bisabolol as a protective agent against epithelial renal cytotoxicity induced by amphotericin B. Life Sci 2021; 291:120271. [PMID: 34974077 DOI: 10.1016/j.lfs.2021.120271] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 12/06/2021] [Accepted: 12/22/2021] [Indexed: 11/30/2022]
Abstract
INTRODUCTION Amphotericin B (AmB), used for systemic fungal infections, has a limited clinical application because of its high nephrotoxicity. Natural antioxidant and anti-inflammatory substances have been widely studied for protection against drug-induced nephrotoxicity. α-Bisabolol (BIS) has demonstrated a nephroprotective effect on both in vitro and in vivo models. AIMS The aim of this work was to evaluate the effect of BIS against AmB-induced nephrotoxicity in vitro. MATERIAL AND METHODS LLC-MK2 cells were pre- and post-treated with non-toxic BIS concentrations and/or AmB IC50 (13.97 μM). Cell viability was assessed by MTT [(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)] assay. Flow cytometry analyses were used to assess cell death mechanism, production of reactive oxidative stress (ROS) and mitochondrial transmembrane potential. Kidney Injury Molecule-1 (KIM-1) levels were measured via ELISA. KEY FINDINGS The present work showed that BIS pretreatment (125; 62.5 and 31.25 μM) increased cell viability when compared to the group treated only with AmB IC50. AmB treatment induced both necrosis (7-AAD-labeled cells) and late apoptosis (AnxV-labeled). BIS was able to prevent the occurrence of these events. These effects were associated with a decrease of ROS accumulation, improving transmembrane mitochondrial potential and protecting against tubular cell damage, highlighted by the inhibition of KIM-1 release after BIS treatment. SIGNIFICANCE BIS presented a potential effect on model of renal cytotoxicity induced by AmB, bringing perspectives for the research of new nephroprotective agents.
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Affiliation(s)
- Emanuel Paula Magalhães
- Postgraduate Program in Pharmaceutical Sciences, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Brenna Pinheiro Silva
- Postgraduate Program in Pharmaceutical Sciences, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Natália Luna Aires
- Department of Clinical and Toxicological Analysis, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Lyanna Rodrigues Ribeiro
- Postgraduate Program in Pharmaceutical Sciences, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Arif Ali
- Postgraduate Program in Pharmacology, Federal University of Ceará, Fortaleza, CE, Brazil
| | | | - João Victor Serra Nunes
- Postgraduate Program in Pharmaceutical Sciences, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Tiago Lima Sampaio
- Department of Clinical and Toxicological Analysis, Federal University of Ceará, Fortaleza, CE, Brazil
| | | | - Alice Maria Costa Martins
- Department of Clinical and Toxicological Analysis, Federal University of Ceará, Fortaleza, CE, Brazil
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Mossoba ME, Sprando RL. In Vitro to In Vivo Concordance of Toxicity Using the Human Proximal Tubule Cell Line HK-2. Int J Toxicol 2020; 39:452-464. [PMID: 32723106 DOI: 10.1177/1091581820942534] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
The renal proximal tubule cell line, human kidney 2 (HK-2), recapitulates many of the functional cellular and molecular characteristics of differentiated primary proximal tubule cells. These features include anchorage dependence, gluconeogenesis capability, and sodium-dependent sugar transport. In order to ascertain how well HK-2 cells can reliably reveal the toxicological profile of compounds having a potential to cause proximal tubule injury in vivo, we sought to evaluate the effects of known proximal tubule toxicants using the HK-2 cell line. We selected 20 pure nephrotoxic compounds that included chemotherapeutic drugs, antibiotics, and heavy metal-containing compounds and evaluated their ability to induce HK-2 cell injury relative to 10 innocuous pure compounds or cell culture media alone. We performed a comprehensive set of in vitro cellular toxicological assays to evaluate cell viability, oxidative stress, mitochondrial integrity, and a specific biomarker of renal injury, Kidney Injury Molecule 1. For each of our selected compounds, we were able to establish a reproducible profile of toxicological outcomes. We compared our results to those described in peer-reviewed publications to understand how well the HK-2 cellular model agrees with overall in vivo rat or human toxicological outcomes. This study begins to address the question of how well in vitro data generated with HK-2 cells can mirror in vivo animal and human outcomes.
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Affiliation(s)
- Miriam E Mossoba
- Division of Toxicology, Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, 4137US Food and Drug Administration, Laurel, MD, USA
| | - Robert L Sprando
- Division of Toxicology, Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, 4137US Food and Drug Administration, Laurel, MD, USA
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Correction to Retraction of: Kidney Injury Molecule-1 Is Up-Regulated in Renal Epithelial Cells in Response to Oxalate In Vitro and in Renal Tissues in Response to Hyperoxaluria In Vivo. PLoS One 2020; 15:e0236263. [PMID: 32658931 PMCID: PMC7357772 DOI: 10.1371/journal.pone.0236263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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Ebohon O, Irabor F, Omoregie ES. Sub-acute toxicity study of methanol extract of Tetrorchidium didymostemon leaves using biochemical analyses and gene expression in Wistar rats. Heliyon 2020; 6:e04313. [PMID: 32637701 PMCID: PMC7327260 DOI: 10.1016/j.heliyon.2020.e04313] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Revised: 06/08/2020] [Accepted: 06/22/2020] [Indexed: 10/31/2022] Open
Abstract
Tetrorchidium didymostemon is widely used by traditional medicine practitioners to manage and treat several diseases. Despite its known ethnomedicinal uses, there are no scientific studies on the toxic effects of this plant. This study was performed to evaluate the potential toxicity of methanol extracts Tetrorchidium didymostemon leaves through sub-acute oral administration in rats. Twenty four (24) male albino rats (Wistar strain) of average weight 150 ± 20 g were randomly divided into 4 groups of 6 rats each. Group 1 was the control while groups 2, 3 and 4 were administered 100, 300 and 600 mg/kg body weight of the plant extracts respectively for 14 consecutively days. The extract did not induce any treatment related changes in body weight, organ/body weight ratio, biochemical parameters (aspartate transaminase, alanine transaminase, total protein, albumin, creatinine and urea), oxidative stress indices (malondialdehyde, superoxide dismutase and reduced glutathione) and histopathology (liver and kidney) of the treated groups when compared to the control. However, at 600 mg/kg body weight dose, the extract caused a significant (p < 0.05) decrease in hemoglobin level, packed cell volume and the expression of albumin gene of rats. Similarly, at 300 and 600 mg/kg body weight, the extract also caused a non-significant (p > 0.05) decrease in red blood cell count. Furthermore, the extract at 100 and 300 mg/kg body weight induced a significant (p < 0.05) increase in the expression of tumor necrosis factor - alpha and kidney injury molecule - 1 (KIM-1) genes. Catalase gene expression especially in the kidney was up-regulated in the groups administered the extract. Our study suggests that oral administration of T. didymostemon leaves extract is relatively safe. However, there is need for caution due to the observed changes in hematological profile, up-regulation of KIM-1 genes as well as down regulation of albumin gene.
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Affiliation(s)
- Osamudiamen Ebohon
- Department of Biochemistry, Faculty of Natural and Applied Sciences, Michael and Cecilia Ibru University, Agbarha-Otor, Delta, Nigeria
| | - Francis Irabor
- Department of Biochemistry, Faculty of Natural and Applied Sciences, Michael and Cecilia Ibru University, Agbarha-Otor, Delta, Nigeria
| | - Ehimwenma Sheena Omoregie
- Malaria Research, Molecular Biology and Toxicology Unit, Department of Biochemistry, Faculty of Life Sciences, University of Benin, PMB 1154, Benin City, Nigeria
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Retraction: Kidney Injury Molecule-1 Is Up-Regulated in Renal Epithelial Cells in Response to Oxalate In Vitro and in Renal Tissues in Response to Hyperoxaluria In Vivo. PLoS One 2020; 15:e0234862. [PMID: 32525956 PMCID: PMC7289383 DOI: 10.1371/journal.pone.0234862] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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Sampaio TL, Menezes RRPPBD, Lima DB, Costa Silva RA, de Azevedo IEP, Magalhães EP, Marinho MM, dos Santos RP, Martins AMC. Involvement of NADPH-oxidase enzyme in the nephroprotective effect of (−)-α-bisabolol on HK2 cells exposed to ischemia – Reoxygenation. Eur J Pharmacol 2019; 855:1-9. [DOI: 10.1016/j.ejphar.2019.04.044] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 04/22/2019] [Accepted: 04/26/2019] [Indexed: 12/14/2022]
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8
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Potić M, Ignjatović I, Ničković VP, Živković JB, Krdžić JD, Mitić JS, Popović D, Ilić IR, Stojanović NM, Sokolović D. Two different melatonin treatment regimens prevent an increase in kidney injury marker-1 induced by carbon tetrachloride in rat kidneys. Can J Physiol Pharmacol 2019; 97:422-428. [PMID: 30730758 DOI: 10.1139/cjpp-2018-0641] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Acute kidney injury is a frequent disorder that can be mimicked by the application of different nephrotoxic agents, including carbon tetrachloride (CCl4), where kidney injury marker-1 (KIM-1) has been recognized as a highly specific marker. Melatonin is one of the most powerful natural antioxidants and has numerous beneficial properties. We evaluated the nephroprotective potential of 2 melatonin treatment regimens (pre- and post-intoxication) in a CCl4-induced acute kidney injury model based on the standard serum parameters, kidney tissue antioxidative capacity, KIM-1 levels, and kidney tissue morphological changes. The two treatment regimens were found to preserve kidney function, as judged from the evaluated standard serum parameters. Only when administered after the intoxication, melatonin preserved total kidney antioxidant capacity; pre-treatment melatonin only preserved reduced glutathione levels. An increase in tissue KIM-1 level was found to be prevented by both treatment regimens, which correlated with the morphological changes seen in the kidney tissues of animals treated with melatonin and CCl4. The findings of our study are in agreement with the known actions of melatonin in relieving kidney tissue oxidative burden, but also contribute to the understanding of its action by preventing an increase in KIM-1.
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Affiliation(s)
- Milan Potić
- a Medical Faculty, University of Niš, Clinical center Niš-Clinic of urology, Niš, Serbia
| | - Ivan Ignjatović
- a Medical Faculty, University of Niš, Clinical center Niš-Clinic of urology, Niš, Serbia
| | | | - Jovan B Živković
- c Faculty of Medicine, University of Priština, Kosovska Mitrovica, Serbia
| | - Jelena D Krdžić
- c Faculty of Medicine, University of Priština, Kosovska Mitrovica, Serbia
| | - Jadranka S Mitić
- c Faculty of Medicine, University of Priština, Kosovska Mitrovica, Serbia
| | - Dejan Popović
- d Faculty of Medicine, University of Niš, Zorana Ðinđića 81, Niš, Serbia
| | - Ivan R Ilić
- d Faculty of Medicine, University of Niš, Zorana Ðinđića 81, Niš, Serbia
| | | | - Dušan Sokolović
- d Faculty of Medicine, University of Niš, Zorana Ðinđića 81, Niš, Serbia
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Cu-bearing stainless steel reduces cytotoxicity and crystals adhesion after ureteral epithelial cells exposing to calcium oxalate monohydrate. Sci Rep 2018; 8:14094. [PMID: 30237503 PMCID: PMC6148291 DOI: 10.1038/s41598-018-32388-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 04/13/2018] [Indexed: 12/24/2022] Open
Abstract
Calcium oxalate monohydrate (COM), which is the main component of encrustation, may result in cell membrane injury. In addition, cellular damage is suggested to be the primary event attributing to COM crystal binding. To study the interaction between cells and crystals after incubating with a Cu-bearing stainless steel (316L-Cu SS), MTS and flow cytometric analyses were used to assess the cellular responses. The results confirmed that 316L-Cu SS could inhibit cytotoxicity and cellular apoptosis of ureteral epithelial cells (UECs) after COM treatment. Furthermore, molecular expressions of Cu/Zn superoxide dismutase (CuZnSOD), which were evaluated by western blot analysis and real-time quantitative PCR (qPCR), indicated that 316L-Cu SS could inhibit the oxidative stress attributing to up-regulating of CuZnSOD. Moreover, the crystal adhesion cytokine CD44 was examined with western blot and qPCR, and the corresponding hyaluronic (HA) secreted into the medium was measured by enzyme-linked immunosorbent assay (ELISA). All results were confirmed that the expressions of cells cultured with 316L-Cu SS were down-regulated, demonstrating the inhibitory performance of 316L-Cu SS against crystal adhesion.
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Amelioration of hyperoxaluria-induced kidney dysfunction by chemical chaperone 4-phenylbutyric acid. Urolithiasis 2018; 47:171-179. [DOI: 10.1007/s00240-018-1064-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Accepted: 06/08/2018] [Indexed: 01/11/2023]
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Collier JB, Schnellmann RG. Extracellular Signal-Regulated Kinase 1/2 Regulates Mouse Kidney Injury Molecule-1 Expression Physiologically and Following Ischemic and Septic Renal Injury. J Pharmacol Exp Ther 2017; 363:419-427. [PMID: 29074644 PMCID: PMC5698947 DOI: 10.1124/jpet.117.244152] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Accepted: 09/27/2017] [Indexed: 01/31/2023] Open
Abstract
The upregulation of kidney injury molecule-1 (KIM-1) has been extensively studied in various renal diseases and following acute injury; however, the initial mechanisms controlling KIM-1 expression remain limited. In this study, KIM-1 expression was examined in mouse renal cell cultures and in two different models of acute kidney injury (AKI), ischemia reperfusion (IR)-induced and lipopolysaccharide (LPS)-induced sepsis. KIM-1 mRNA increased in both AKI models, and pharmacological inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) signaling attenuated injury-induced KIM-1 expression in the renal cortex. Toll-like receptor 4 knockout (TLR4KO) mice exhibited reduced ERK1/2 phosphorylation and attenuated KIM-1 mRNA after LPS exposure. TLR4KO mice were not protected from IR-induced ERK1/2 phosphorylation and upregulation of KIM-1 mRNA. Following renal IR injury, phosphorylation of signal transducer and activator of transcription 3 (STAT3) at serine 727 and tyrosine 705 increased downstream from ERK1/2 activation. Because phosphorylated STAT3 is a transcriptional upregulator of KIM-1 and inhibition of ERK1/2 attenuated increases in STAT3 phosphorylation, we suggest an ERK1/2-STAT3-KIM-1 pathway following renal injury. Finally, ERK1/2 inhibition in naive mice decreased KIM-1 mRNA and nuclear STAT3 phosphorylation in the cortex, indicating homeostatic regulation of KIM-1. These findings reveal renal ERK1/2 as an important initial regulator of KIM-1 expression in IR and septic AKI and at a physiologic level.Visual Abstract.Proposed mechanism of IR, LPS, and ROS-induced renal damage that initiates ERK1/2 and STAT3 phosphorylation. STAT3 then binds to the KIM-1 promoter and increases KIM-1 mRNA. By preventing ERK1/2 phosphorylation following renal injury, STAT3 phosphorylation is decreased, leading to less phosphorylated STAT3 within the nucleus, and subsequently less KIM-1 mRNA increases post injury.
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Affiliation(s)
- Justin B Collier
- Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina (J.B.C.); and Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona (R.G.S.)
| | - Rick G Schnellmann
- Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina (J.B.C.); and Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona (R.G.S.)
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Albert A, Tiwari V, Paul E, Ponnusamy S, Ganesan D, Prabhakaran R, Mariaraj Sivakumar S, Govindan Sadasivam S. Oral administration of oxalate-enriched spinach extract as an improved methodology for the induction of dietary hyperoxaluric nephrocalcinosis in experimental rats. Toxicol Mech Methods 2017; 28:195-204. [DOI: 10.1080/15376516.2017.1388459] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Affiliation(s)
- Abhishek Albert
- Department of Biochemistry, Centre for Excellence in Genomics Science, School of Biological Sciences, Madurai Kamaraj University, Madurai, India
| | - Vidhi Tiwari
- Department of Biochemistry, Centre for Excellence in Genomics Science, School of Biological Sciences, Madurai Kamaraj University, Madurai, India
| | - Eldho Paul
- Department of Biochemistry, Centre for Excellence in Genomics Science, School of Biological Sciences, Madurai Kamaraj University, Madurai, India
| | - Sasikumar Ponnusamy
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, NY, USA
| | - Divya Ganesan
- Department of Biochemistry, Centre for Excellence in Genomics Science, School of Biological Sciences, Madurai Kamaraj University, Madurai, India
| | - Rajkumar Prabhakaran
- Department of Biochemistry, Centre for Excellence in Genomics Science, School of Biological Sciences, Madurai Kamaraj University, Madurai, India
| | - Selvi Mariaraj Sivakumar
- Department of Biochemistry, Centre for Excellence in Genomics Science, School of Biological Sciences, Madurai Kamaraj University, Madurai, India
| | - Selvam Govindan Sadasivam
- Department of Biochemistry, Centre for Excellence in Genomics Science, School of Biological Sciences, Madurai Kamaraj University, Madurai, India
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Mossoba ME, Vohra S, Toomer H, Pugh-Bishop S, Keltner Z, Topping V, Black T, Olejnik N, Depina A, Belgrave K, Sprando J, Njorge J, Flynn TJ, Wiesenfeld PL, Sprando RL. Comparison of diglycolic acid exposure to human proximal tubule cells in vitro and rat kidneys in vivo. Toxicol Rep 2017; 4:342-347. [PMID: 28959658 PMCID: PMC5615145 DOI: 10.1016/j.toxrep.2017.06.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Revised: 06/19/2017] [Accepted: 06/22/2017] [Indexed: 01/13/2023] Open
Abstract
Diglycolic acid (DGA) is an indirect food additive. DGA was tested for renal cell toxicity in vitro using HK-2 cells. Evaluation of toxicity included cellular and mitochondrial effects. In vitro data are highly concordant with in vivo outcomes. Diglycolic acid (DGA) is present in trace amounts in our food supply and is classified as an indirect food additive linked with the primary GRAS food additive carboxymethyl cellulose (CMC). Carboxymethyl starches are used as a filler/binder excipient in dietary supplement tablets and a thickening ingredient in many other processed foods. We sought to utilize the human proximal tubule HK-2 cell line as an in vitro cellular model system to evaluate its acute nephrotoxicity of DGA. We found that DGA was indeed toxic to HK-2 cells in all in vitro assays in our study, including a highly sensitive Luminex assay that measures levels of an in vitro biomarker of kidney-specific toxicity, Kidney Injury Molecule 1 (KIM-1). Interestingly, in vitro KIM-1 levels also correlated with in vivo KIM-1 levels in urine collected from rats treated with DGA by daily oral gavage. The use of in vitro and in vivo models towards understanding the effectiveness of an established in vitro system to predict in vivo outcomes would be particularly useful in rapidly screening compounds that are suspected to be unsafe to consumers. The merit of the HK-2 cell model in predicting human toxicity and accelerating the process of food toxicant screening would be especially important for regulatory purposes. Overall, our study not only revealed the value of HK-2 in vitro cell model for nephrotoxicity evaluation, but also uncovered some of the mechanistic aspects of the human proximal tubule injury that DGA may cause.
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Affiliation(s)
- Miriam E. Mossoba
- Corresponding author at: US FDA, MOD-1 Laboratories, 8301 Muirkirk Rd., HFS-025, Lab 1406, Laurel, MD 20708, United States.
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Mossoba ME, Vohra SN, Wiesenfeld PL, Sprando RL. Nephrotoxicity of Combining 2-Phenethylamine and N, N-Dimethyl-β-Phenethylamine. ACTA ACUST UNITED AC 2016. [DOI: 10.1089/aivt.2015.0023] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Affiliation(s)
- Miriam E. Mossoba
- Division of Toxicology, Neurotoxicology and In vitro Toxicology Branch, Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, Laurel, Maryland
| | - Sanah N. Vohra
- Division of Toxicology, Neurotoxicology and In vitro Toxicology Branch, Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, Laurel, Maryland
| | - Paddy L. Wiesenfeld
- Division of Toxicology, Neurotoxicology and In vitro Toxicology Branch, Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, Laurel, Maryland
| | - Robert L. Sprando
- Division of Toxicology, Neurotoxicology and In vitro Toxicology Branch, Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, Laurel, Maryland
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Mossoba ME, Flynn TJ, Vohra S, Wiesenfeld PL, Sprando RL. Human kidney proximal tubule cells are vulnerable to the effects of Rauwolfia serpentina. Cell Biol Toxicol 2016; 31:285-93. [PMID: 26838987 DOI: 10.1007/s10565-016-9311-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Accepted: 01/15/2016] [Indexed: 11/25/2022]
Abstract
Rauwolfia serpentina (or Snake root plant) is a botanical dietary supplement marketed in the USA for maintaining blood pressure. Very few studies have addressed the safety of this herb, despite its wide availability to consumers. Its reported pleiotropic effects underscore the necessity for evaluating its safety. We used a human kidney cell line to investigate the possible negative effects of R. serpentina on the renal system in vitro, with a specific focus on the renal proximal tubules. We evaluated cellular and mitochondrial toxicity, along with a variety of other kidney-specific toxicology biomarkers. We found that R. serpentina was capable of producing highly detrimental effects in our in vitro renal cell system. These results suggest more studies are needed to investigate the safety of this dietary supplement in both kidney and other target organ systems.
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Affiliation(s)
- Miriam E Mossoba
- Center for Food Safety and Applied Nutrition (CFSAN), Office of Applied Research and Safety Assessment (OARSA), Division of Toxicology (DOT), Neurotoxicology and in vitro Toxicology Branch (NIVTB), U.S. Food and Drug Administration (US FDA), 8301 Muirkirk Rd., Laurel, MD, 20708, USA.
- MOD-1 Laboratories, US FDA, 8301 Muirkirk Rd., HFS-025, Lab 1406, Laurel, MD, 20708, USA.
| | - Thomas J Flynn
- Center for Food Safety and Applied Nutrition (CFSAN), Office of Applied Research and Safety Assessment (OARSA), Division of Toxicology (DOT), Neurotoxicology and in vitro Toxicology Branch (NIVTB), U.S. Food and Drug Administration (US FDA), 8301 Muirkirk Rd., Laurel, MD, 20708, USA
| | - Sanah Vohra
- Center for Food Safety and Applied Nutrition (CFSAN), Office of Applied Research and Safety Assessment (OARSA), Division of Toxicology (DOT), Neurotoxicology and in vitro Toxicology Branch (NIVTB), U.S. Food and Drug Administration (US FDA), 8301 Muirkirk Rd., Laurel, MD, 20708, USA
| | - Paddy L Wiesenfeld
- Center for Food Safety and Applied Nutrition (CFSAN), Office of Applied Research and Safety Assessment (OARSA), Division of Toxicology (DOT), Neurotoxicology and in vitro Toxicology Branch (NIVTB), U.S. Food and Drug Administration (US FDA), 8301 Muirkirk Rd., Laurel, MD, 20708, USA
| | - Robert L Sprando
- Center for Food Safety and Applied Nutrition (CFSAN), Office of Applied Research and Safety Assessment (OARSA), Division of Toxicology (DOT), Neurotoxicology and in vitro Toxicology Branch (NIVTB), U.S. Food and Drug Administration (US FDA), 8301 Muirkirk Rd., Laurel, MD, 20708, USA
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Urinary kidney injury molecule-1 levels in renal stone patients. World J Urol 2016; 34:1311-6. [DOI: 10.1007/s00345-016-1765-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Accepted: 01/06/2016] [Indexed: 12/23/2022] Open
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Wilmer MJ, Ng CP, Lanz HL, Vulto P, Suter-Dick L, Masereeuw R. Kidney-on-a-Chip Technology for Drug-Induced Nephrotoxicity Screening. Trends Biotechnol 2015; 34:156-170. [PMID: 26708346 DOI: 10.1016/j.tibtech.2015.11.001] [Citation(s) in RCA: 247] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Revised: 11/02/2015] [Accepted: 11/04/2015] [Indexed: 02/06/2023]
Abstract
Improved model systems to predict drug efficacy, interactions, and drug-induced kidney injury (DIKI) are crucially needed in drug development. Organ-on-a-chip technology is a suitable in vitro system because it reproduces the 3D microenvironment. A kidney-on-a-chip can mimic the structural, mechanical, transport, absorptive, and physiological properties of the human kidney. In this review we address the application of state-of-the-art microfluidic culturing techniques, with a focus on culturing kidney proximal tubules, that are promising for the detection of biomarkers that predict drug interactions and DIKI. We also discuss high-throughput screening and the challenges for in vitro to in vivo extrapolation (IVIVE) that will need to be overcome for successful implementation.
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Affiliation(s)
- Martijn J Wilmer
- Department of Pharmacology and Toxicology, Radboudumc, PO Box 9101, Nijmegen, HB 6500 The Netherlands.
| | - Chee Ping Ng
- MIMETAS BV, JH Oortweg 19, Leiden, CH, 2333 The Netherlands
| | | | - Paul Vulto
- MIMETAS BV, JH Oortweg 19, Leiden, CH, 2333 The Netherlands
| | - Laura Suter-Dick
- University of Applied Sciences Northwestern Switzerland, School of Life Sciences, Gründenstrasse 40, 4132 Muttenz, Switzerland
| | - Rosalinde Masereeuw
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, Utrecht, CG 3584 The Netherlands
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Mossoba ME, Flynn TJ, Vohra SN, Wiesenfeld PL, Sprando RL. In vitro exposure of Adhatoda zeylanica to human renal cells lacks acute toxicity. Toxicol Rep 2015; 3:15-20. [PMID: 28959522 PMCID: PMC5615422 DOI: 10.1016/j.toxrep.2015.11.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Revised: 10/25/2015] [Accepted: 11/12/2015] [Indexed: 11/17/2022] Open
Abstract
Adhatoda zeylanica is a dietary supplement ingredient present in several types of dietary supplements, including weight loss, respiratory relief, and immune regulating products. Due to its reported wide range of uses in folk medicine, it was hypothesized that it may have the potential to target multiple organs and lead to a range of toxicity features. As a preliminary evaluation of the safety of this herbal ingredient, an investigation into its effects on the kidney was sought. An in vitro study of its potential nephrotoxicity using the HK-2 human proximal tubule cell line in a variety of functional indicators was performed to capture both general forms of cellular toxicity as well as ones that are specific to proximal tubules. A. zeylanica was only capable of inducing detrimental short-term toxicity to HK-2 cells at relatively high treatment concentrations when exposed directly to the cells. The lack of acute and potent toxicity of A. zeylanica under our experimental conditions calls for further studies to better define its toxicant threshold and establish safe dosage levels.
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Affiliation(s)
- Miriam E Mossoba
- U.S Food and Drug Administration (U.S. FDA), Center for Food Safety and Applied Nutrition (CFSAN), Office of Applied Research and Safety Assessment (OARSA), Division of Toxicology (DOT), Neurotoxicology and In vitro Toxicology Branch (NIVTB), 8301 Muirkirk Rd., Laurel, MD 20708, United States
| | - Thomas J Flynn
- U.S Food and Drug Administration (U.S. FDA), Center for Food Safety and Applied Nutrition (CFSAN), Office of Applied Research and Safety Assessment (OARSA), Division of Toxicology (DOT), Neurotoxicology and In vitro Toxicology Branch (NIVTB), 8301 Muirkirk Rd., Laurel, MD 20708, United States
| | - Sanah N Vohra
- U.S Food and Drug Administration (U.S. FDA), Center for Food Safety and Applied Nutrition (CFSAN), Office of Applied Research and Safety Assessment (OARSA), Division of Toxicology (DOT), Neurotoxicology and In vitro Toxicology Branch (NIVTB), 8301 Muirkirk Rd., Laurel, MD 20708, United States
| | - Paddy L Wiesenfeld
- U.S Food and Drug Administration (U.S. FDA), Center for Food Safety and Applied Nutrition (CFSAN), Office of Applied Research and Safety Assessment (OARSA), Division of Toxicology (DOT), Neurotoxicology and In vitro Toxicology Branch (NIVTB), 8301 Muirkirk Rd., Laurel, MD 20708, United States
| | - Robert L Sprando
- U.S Food and Drug Administration (U.S. FDA), Center for Food Safety and Applied Nutrition (CFSAN), Office of Applied Research and Safety Assessment (OARSA), Division of Toxicology (DOT), Neurotoxicology and In vitro Toxicology Branch (NIVTB), 8301 Muirkirk Rd., Laurel, MD 20708, United States
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19
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Glew RH, Sun Y, Horowitz BL, Konstantinov KN, Barry M, Fair JR, Massie L, Tzamaloukas AH. Nephropathy in dietary hyperoxaluria: A potentially preventable acute or chronic kidney disease. World J Nephrol 2014; 3:122-142. [PMID: 25374807 PMCID: PMC4220346 DOI: 10.5527/wjn.v3.i4.122] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2014] [Revised: 06/12/2014] [Accepted: 08/29/2014] [Indexed: 02/06/2023] Open
Abstract
Hyperoxaluria can cause not only nephrolithiasis and nephrocalcinosis, but also renal parenchymal disease histologically characterized by deposition of calcium oxalate crystals throughout the renal parenchyma, profound tubular damage and interstitial inflammation and fibrosis. Hyperoxaluric nephropathy presents clinically as acute or chronic renal failure that may progress to end-stage renal disease (ESRD). This sequence of events, well recognized in the past in primary and enteric hyperoxalurias, has also been documented in a few cases of dietary hyperoxaluria. Estimates of oxalate intake in patients with chronic dietary hyperoxaluria who developed chronic kidney disease or ESRD were comparable to the reported average oxalate content of the diets of certain populations worldwide, thus raising the question whether dietary hyperoxaluria is a primary cause of ESRD in these regions. Studies addressing this question have the potential of improving population health and should be undertaken, alongside ongoing studies which are yielding fresh insights into the mechanisms of intestinal absorption and renal excretion of oxalate, and into the mechanisms of development of oxalate-induced renal parenchymal disease. Novel preventive and therapeutic strategies for treating all types of hyperoxaluria are expected to develop from these studies.
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Cunha NB, Kawano PR, Padovani CR, Lima FDO, Bernardes S, Magalhães ES, Amaro CRP, Amaro JL. Nephrocalcinosis induced by hyperoxaluria in rats. Acta Cir Bras 2013; 28:496-501. [DOI: 10.1590/s0102-86502013000700004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2013] [Accepted: 06/11/2013] [Indexed: 11/22/2022] Open
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