Simple graphical approach to investigate differences in transepithelial paracellular leak pathway permeability

Monaco, Ashley; Axis, Josephine; Amsler, Kurt

doi:10.14814/phy2.15202

Cited by 3 publications

(2 citation statements)

References 59 publications

(107 reference statements)

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“…Although other factors such as hydrogen peroxide, cytokines, mechanical stress, chemicals, and pathogenic bacteria have been also reported as causes of leak pathway permeability changes, little is understood about the regulatory mechanisms and properties of the leak pathway 57 , 58 . On the other hand, TJ proteins are known to be involved in the regulation of the leak pathway 59 , 60 .…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, TJ proteins are known to be involved in the regulation of the leak pathway 59 , 60 . ZO-1, a TJ scaffold protein, is considered a regulator of the leak pathway, and ZO-1 depletion was reported to disrupt the leak pathway 9 , 57 . ZO-1 interacts with the transmembrane proteins claudin and occludin, with cytoskeletal F-actin, and with myosin and other signaling proteins and is essential for TJ and cytoskeletal structure; however, its role is not clearly understood 9 .…”

Section: Discussionmentioning

confidence: 99%

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Beneficial effect of heat-killed Lactiplantibacillus plantarum L-137 on intestinal barrier function of rat small intestinal epithelial cells

Watanabe,

Nakai,

Ohara

et al. 2024

Sci Rep

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Heat-killed Lactiplantibacillus plantarum L-137 (HK L-137) has been suggested to enhance the intestinal barrier in obese mice, leading to improvement of metabolic abnormalities and adipose tissue inflammation, and in healthy humans with overweight, leading to improvement of systemic inflammation. However, its detailed mechanism of action has not been clarified. Therefore, this study investigated the effects of HK L-137 on the permeability of rat small intestinal epithelial IEC-6 cells, tight junction-related gene and protein expression and localization, and intracellular signaling pathways involved in barrier function. Treatment of IEC-6 cells with HK L-137 for 26 h significantly reduced the permeability to fluorescein isothiocyanate-dextran (FD-4). HK L-137 also increased gene and protein expression of zonula occludens-1 (ZO-1), an important tight junction protein, without affecting the localization. Furthermore, inhibition of the extracellular signal-regulated kinase (ERK)1/2 pathway in IEC-6 cells canceled the HK L-137-related reduction in permeability to FD-4. Phosphorylation of ERK in IEC-6 cells was induced 15 min after the addition of HK L-137. These results suggest that HK L-137 reduces intestinal permeability partly through activating the ERK pathway and increasing expression of the ZO-1 gene and protein. Enhancement of intestinal barrier function with HK L-137 might be effective in preventing and treating leaky gut, for which no specific therapeutic tool has been established.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Beneficial effect of heat-killed Lactiplantibacillus plantarum L-137 on intestinal barrier function of rat small intestinal epithelial cells

Watanabe,

Nakai,

Ohara

et al. 2024

Sci Rep

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Na-caprate-induced increase in MDCK II epithelial cell leak pathway permeability and opening number is associated with disruption of basal F-actin organization

Rana,

Nasr,

Chang

et al. 2024

American Journal of Physiology-Cell Physiology

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Confluent populations of the epithelial cell line, MDCK II, develop circumferential tight junctions joining adjacent cells to create a barrier to the paracellular movement of solutes and water. Treatment of MDCK II cell populations from the apical surface with 1 mM Na-caprate increased permeability to macromolecules (Leak Pathway) without increasing monolayer disruption or cell death. Graphical analysis of the apparent permeability versus solute Stokes radius for a size range of fluorescein-dextran species indicates apical 1 mM Na-caprate enhances Leak Pathway permeability by increasing the number of Leak Pathway openings without significantly affecting opening size. Na-caprate treatment did not alter the content of any tight junction protein examined. Treatment of MDCK II cell populations with apical 1 mM Na-caprate disrupted basal F-actin stress fibers and decreased the tortuosity of the tight junctions. Treatment of MDCK II cell populations with blebbistatin, a myosin ATPase inhibitor, alone had little effect on Leak Pathway permeability but synergistically increased Leak Pathway permeability when added with 1 mM Na-caprate. Na-caprate exhibited a similar ability to increase Leak Pathway permeability in wild type MDCK II cell monolayers and ZO-1 knockdown MDCK II cell monolayers but an enhanced ability to increase Leak Pathway permeability in monolayers of TOCA-1 knockout MDCK II cells. These results demonstrate that Na-caprate increases MDCK II cell population Leak Pathway permeability by increasing the number of Leak Pathway openings. This action is likely mediated by alterations in F-actin organization, primarily involving disruption of basal F-actin stress fibers.

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Simple graphical approach to investigate differences in transepithelial paracellular leak pathway permeability

Monaco

Axis

Amsler

2022

Physiological Reports

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Although many studies have reported differences in epithelial paracellular Leak Pathway permeability following genetic manipulations and treatment with various agents, the basis for these differences remains mostly unclear. Two primary mechanisms which could underlie differences in Leak Pathway permeability are differences in the density of Leak Pathway openings and differences in the opening size. Using a computational approach, we demonstrate that these two possibilities can be readily distinguished graphically by comparing the apparent paracellular permeabilities of a size panel of solutes measured across different cell layers. Using this approach, we demonstrated that depletion of ZO‐1 protein in MDCK Type II renal epithelial cells decreased Leak Pathway opening size and increased opening density. Depletion of ZO‐2 protein either had no effect or minimally decreased opening size and did not markedly change opening density. Comparison of MDCK Type II cells with MDCK Type I cells revealed that Type I cells exhibited a substantially smaller Leak Pathway permeability than did Type II cells. This lower permeability was due to a decrease in opening density with little or no change in opening size. These results demonstrate the utility of this approach to provide insights into the basis for observed differences in epithelial Leak Pathway permeability. This approach has wide applications including analysis of the molecular basis for Leak Pathway permeability, the effects of specific manipulations on Leak Pathway permeability properties, and the effects of permeation enhancers on Leak Pathway permeability properties.

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Simple graphical approach to investigate differences in transepithelial paracellular leak pathway permeability

Cited by 3 publications

References 59 publications

Beneficial effect of heat-killed Lactiplantibacillus plantarum L-137 on intestinal barrier function of rat small intestinal epithelial cells

Beneficial effect of heat-killed Lactiplantibacillus plantarum L-137 on intestinal barrier function of rat small intestinal epithelial cells

Na-caprate-induced increase in MDCK II epithelial cell leak pathway permeability and opening number is associated with disruption of basal F-actin organization

Simple graphical approach to investigate differences in transepithelial paracellular leak pathway permeability

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