Renal tight junction proteins are decreased in cisplatin-induced nephrotoxicity in rats

Trujillo, Joyce; Molina‐Jijón, Eduardo; Medina-Campos, Omar Noel; Rodríguez-Muñóz, Rafael; Reyes, José L.; Loredo, Maria; Tapia, Edilia; Sánchez‐Lozada, Laura G.; Barrera-Oviedo, Diana

doi:10.3109/15376516.2014.948248

Cited by 20 publications

(22 citation statements)

References 33 publications

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“…Claudin 2 expression is regulated by components of the immune system (including IL-2, tumour necrosis factor (TNF), IL-13, IL-15, and IL-17) and growth factor signalling (including pro-epidermal growth factor (EGF), hepatocyte growth factor (HGF), extracellular signal-regulated kinase 1 (ERK1; also known as MAPK3), ERK2, and the RACα serine/threonine-protein kinase (AKT) pathways) 54 . Under pathophysiological conditions such as cisplatin-induced nephrotoxicity, ischaemic injury, or metabolic acidosis, claudin 2 expression is reduced, resulting in impaired paracellular transport of cations, which may contribute to disruption of the proximal tubule epithelium 55,56 . Tight junction injury can be visualized in vitro by tracking immunofluorescence or leakage of labelled inulin.…”

Section: Characterization Of Cellular Modelsmentioning

confidence: 99%

Advances in predictive in vitro models of drug-induced nephrotoxicity

et al. 2018

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In vitro screens for nephrotoxicity are currently poorly predictive of toxicity in humans. Although the functional proteins that are expressed by nephron tubules and mediate drug susceptibility are well known, current in vitro cellular models poorly replicate both the morphology and the function of kidney tubules and therefore fail to demonstrate injury responses to drugs that would be nephrotoxic in vivo. Advances in protocols to enable the directed differentiation of pluripotent stem cells into multiple renal cell types and the development of microfluidic and 3D culture systems have opened a range of potential new platforms for evaluating drug nephrotoxicity. Many of the new in vitro culture systems have been characterized by the expression and function of transporters, enzymes, and other functional proteins that are expressed by the kidney and have been implicated in drug-induced renal injury. In vitro platforms that express these proteins and exhibit molecular biomarkers that have been used as readouts of injury demonstrate improved functional maturity compared with static 2D cultures and represent an opportunity to model injury to renal cell types that have hitherto received little attention. As nephrotoxicity screening platforms become more physiologically relevant, they will facilitate the development of safer drugs and improved clinical management of nephrotoxicants.

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Section: Characterization Of Cellular Modelsmentioning

confidence: 99%

Advances in predictive in vitro models of drug-induced nephrotoxicity

et al. 2018

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“…BUN, plasma creatinine, N-acetyl-β-D-glucosaminidase (NAG), NGAL, KIM-1 were used as markers of renal injury 32,48 . BUN and plasma creatinine were determined with commercial kits from Spinreact® 49 .…”

Section: Determination Of Renal Functionmentioning

confidence: 99%

“…We previously reported that occludin and claudin-2 expressions are decreased in CISinduced nephrotoxicity associated with oxidative stress derived in part to an increased production of superoxide anion (O 2 •-) by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity 32,40 . The potential effect of curcumin against TGFβ1-induced EMT and fibrosis, and alterations in TJ and AJ structure and function has not been evaluated in CIS-induced nephrotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Curcumin prevents cisplatin-induced decrease in the tight and adherens junctions: relation to oxidative stress

et al. 2016

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Curcumin is a polyphenol and cisplatin is an antineoplastic agent that induces nephrotoxicity associated with oxidative stress, apoptosis, fibrosis and decrease in renal tight junction (TJ) proteins. The potential effect of curcumin against alterations in TJ structure and function has not been evaluated in cisplatin-induced nephrotoxicity. The present study explored whether curcumin is able to prevent the cisplatin-induced fibrosis and decreased expression of the TJ and adherens junction (AJ) proteins occludin, claudin-2 and E-cadherin in cisplatin-induced nephrotoxicity. Curcumin (200 mg kg(-1)) was administered in three doses, and rats were sacrificed 72 h after cisplatin administration. Curcumin was able to scavenge, in a concentration-dependent way, superoxide anion, hydroxyl radical, peroxyl radical, singlet oxygen, peroxynitrite anion, hypochlorous acid and hydrogen peroxide. Cisplatin-induced renal damage was associated with alterations in plasma creatinine, expression of neutrophil gelatinase-associated lipocalin and of kidney injury molecule-1, histological damage, increase in apoptosis, fibrosis (evaluated by transforming growth factor β1, collagen I and IV and α-smooth muscle actin expressions), increase in oxidative/nitrosative stress (evaluated by Hsp70/72 expression, protein tyrosine nitration, superoxide anion production in isolated glomeruli and proximal tubules, and protein levels of NADPH oxidase subunits p47(phox) and gp91(phox), protein kinase C β2, and Nrf2) as well as by decreased expression of occludin, claudin-2, β-catenin and E-cadherin. Curcumin treatment prevented all the above-described alterations. The protective effect of curcumin against cisplatin-induced fibrosis and decreased proteins of the TJ and AJ was associated with the prevention of glomerular and proximal tubular superoxide anion production induced by NADPH oxidase activity.

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“…8,9 There are many molecular mechanisms associated with long-term nephrotoxicity induced by cisplatin, including oxidative stress and TJ protein expression changes, apoptosis, inflammation, and fibrogenesis. [10][11][12] Among these nephrotoxic mechanisms, the loss of F-actin stress fibers is known to be an early step of cisplatin-mediated nephrotoxicity, which leads to cell detachment. 13,14 In addition, after injury or renal tubular cell differentiation, several markers have been reported to increase their concentration: podocalyxin (a podocyte marker), multidrug and toxin extrusion proteins 1 and 2 (MATE; responsible for cisplatin excretion into urine), organic cation and organic anion transporters (OCT and OAT, responsible for the accumulation of cisplatin from the blood into proximal tubules), and kidney injury molecule-1 (KIM-1, transmembrane protein).…”

Section: Introductionmentioning

confidence: 99%

“…Traditionally, the techniques used to detect cellular damage in nephrotoxic events involve imaging approaches for visualizing expression of cell markers, cell viability, apoptosis assays, quantitative reverse transcription-PCR, and omics approaches. 12,29 Although these methods provide information about the mechanisms of toxicity of the drugs, they are time-consuming, require the use of chromophores or fluorophores, and, most importantly, are usually limited to providing ''end-point'' data rather than real-time monitoring. An emerging trend in the field of in vitro toxicology is to use electronic impedance spectroscopy (EIS) for monitoring cells.…”

Section: Introductionmentioning

confidence: 99%

Early Detection of NephrotoxicityIn VitroUsing a Transparent Conducting Polymer Device

Huerta

Rivnay

RamuzMarc

et al. 2016

Applied In Vitro Toxicology

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Electrical methods for monitoring cell toxicity are becoming increasingly popular because of their amenability for longer-term, continuous, and label-free monitoring. Microfabrication techniques are also opening the way for miniaturization of devices and integration with microphysiometer or lab-on-chip-type devices. In the present work, we demonstrate the use of a transparent conducting polymer device, termed the ''organic electrochemical transistor'' (OECT), which we have used to monitor the effects of a subset of known nephrotoxicants (cisplatin, tobramycin, and gentamycin) on cell integrity in vitro. Based on a similar principle to traditional electronic impedance spectroscopy, the OECT provides an even more sensitive way to detect small changes in ionic currents in an electrolyte, as a result of inherent amplification of signal provided thanks to the transistor format. The device monitored the ability of the human renal proximal tubular epithelial cells, a human primary cell culture model of the kidney proximal tubule, to act as a barrier to ion flow (analogous to transepithelial resistance), even though this was not possible with a commercially available instrument (cellZscope). Further, the device demonstrated extremely rapid nephrotoxicity even at low concentrations, the transparency of the device allowed in situ monitoring of cells on the device, as well as immunofluorescence staining of key biomarkers of kidney tubule function: KIM-1 and ZO-1. Correlation of electrical and optical data was demonstrated as a powerful tool for validation of the method. In summary, the OECT is presented as an extremely versatile tool for highly sensitive nephrotoxicity monitoring, amenable for future integration into microfabricated lab-on-chip platforms.

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Renal tight junction proteins are decreased in cisplatin-induced nephrotoxicity in rats

Abstract: CP altered the TJ proteins expression and localization in the proximal tubule that was associated with oxidative/nitrosative stress.

Cited by 20 publications

References 33 publications

Advances in predictive in vitro models of drug-induced nephrotoxicity

Advances in predictive in vitro models of drug-induced nephrotoxicity

Curcumin prevents cisplatin-induced decrease in the tight and adherens junctions: relation to oxidative stress

Early Detection of NephrotoxicityIn VitroUsing a Transparent Conducting Polymer Device

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