Comparison of diglycolic acid exposure to human proximal tubule cells in vitro and rat kidneys in vivo

Mossoba, Miriam E.; Vohra, Sanah; Toomer, Howard; Pugh-Bishop, Shelia; Keltner, Zachary; Topping, Vanessa; Black, T.N.; Olejnik, Nicholas; DePina, Ana S.; Belgrave, Kathleen; Sprando, Jessica; Njorge, Joyce; Flynn, Tom; Wiesenfeld, Paddy L.; Sprando, Robert L.

doi:10.1016/j.toxrep.2017.06.011

Cited by 5 publications

(2 citation statements)

References 29 publications

(47 reference statements)

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“…The relative mildness of 3-MCPD is also supported by our finding that KIM-1 levels neither appreciably rose in response to 3-MCPD treatment concentration nor to exposure duration. Although KIM-1 is an FDA-qualified biomarker of renal injury in vivo (Bonventre et al, 2010), it has also been demonstrated by multiple research groups to be a valuable in vitro cellular biomarker of proximal tubule cell injury (Luo et al, 2016;Mossoba et al, 2017;Veach and Wilson, 2018). KIM-1 expression is triggered in proximal tubule cells in response to a wide variety of toxic insults and has been shown to be part of a mitogenactivated protein kinase (MAPK)-mediated cell regenerative mechanism to repair injured cells (Song et al, 2019;Zhang and Cai, 2016).…”

Section: Discussionmentioning

confidence: 99%

Long-term <i>in vitro</i> effects of exposing the human HK-2 proximal tubule cell line to 3-monochloropropane-1,2-diol

et al. 2020

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Monochloropropane-1,2-diol (3-MCPD) is a food processing contaminant in the U.S. food supply, detected in infant formula. In vivo rodent model studies have identified a variety of possible adverse outcomes from 3-MCPD exposure including renal effects like increased kidney weights, tubular hyperplasia, kidney tubular necrosis, and chronic progressive nephropathy. Given the lack of available in vivo toxicological assessments of 3-MCPD in humans and the limited availability of in vitro human cell studies, the health effects of 3-MCPD remain unclear. We used in vitro human proximal tubule cells represented by the HK-2 cell line to compare short-and long-term consequences to continuous exposure to this compound. After periodic lengths of exposure (0-100 mM) ranging from 1 to 16 days, we evaluated cell viability, mitochondrial integrity, oxidative stress, and a specific biomarker of proximal tubule injury, Kidney Injury Molecule-1 (KIM-1). Overall, we found that free 3-MCPD was generally more toxic at high concentrations or extended durations of exposure, but that its overall ability to induce cell injury was limited in this in vitro system. Further experiments will be needed to conduct a comprehensive safety assessment in infants who may be exposed to 3-MCPD through consumption of infant formula, as human renal physiology changes significantly during development.

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Section: Discussionmentioning

confidence: 99%

Long-term <i>in vitro</i> effects of exposing the human HK-2 proximal tubule cell line to 3-monochloropropane-1,2-diol

et al. 2020

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“…However, it bears the drawback of inefficiency and high cost. Although animal models exhibit high specificity for nephrotoxicity in drug dosage or safety pharmacology investigations, low sensitivity is also present [ 5 ]. In addition, due to species differences, many lead compounds with better potential were rejected as a result of their nephrotoxicity in animals [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Functional Evaluation and Nephrotoxicity Assessment of Human Renal Proximal Tubule Cells on a Chip

Jing

Liu²,

Li³

et al. 2022

Biosensors

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An in vitro human renal proximal tubule model that represents the proper transporter expression and pronounced epithelial polarization is necessary for the accurate prediction of nephrotoxicity. Here, we constructed a high-throughput human renal proximal tubule model based on an integrated biomimetic array chip (iBAC). Primary human renal proximal tubule epithelial cells (hRPTECs) cultured on this microfluidic platform were able to form a tighter barrier, better transporter function and more sensitive nephrotoxicity prediction than those on the static Transwell. Compared with the human immortalized HK2 model, the hRPTECs model on the chip gained improved apical-basolateral polarization, barrier function and transporter expression. Polymyxin B could induce nephrotoxicity not only from the apical of the hRPTECs, but also from the basolateral side on the iBAC. However, other chemotherapeutic agents, such as doxorubicin and sunitinib, only induced nephrotoxicity from the apical surface of the hRPTECs on the iBAC. In summary, our renal proximal tubule model on the chip exhibits improved epithelial polarization and membrane transporter activity, and can be implemented as an effective nephrotoxicity-screening toolkit.

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Genetically Engineered Human Kidney Cells for Real-Time Cytotoxicity Testing In Vitro

et al. 2020

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Comparison of diglycolic acid exposure to human proximal tubule cells in vitro and rat kidneys in vivo

Abstract: Graphical abstract

Cited by 5 publications

References 29 publications

Long-term <i>in vitro</i> effects of exposing the human HK-2 proximal tubule cell line to 3-monochloropropane-1,2-diol

Long-term <i>in vitro</i> effects of exposing the human HK-2 proximal tubule cell line to 3-monochloropropane-1,2-diol

Functional Evaluation and Nephrotoxicity Assessment of Human Renal Proximal Tubule Cells on a Chip

Genetically Engineered Human Kidney Cells for Real-Time Cytotoxicity Testing In Vitro

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