Endotoxemia alters tight junction gene and protein expression in the kidney

Eadon, Michael T.; Hack, Bradley K.; Xu, Chang; Ko, Benjamin; Toback, F. Gary; Cunningham, Patrick N.

doi:10.1152/ajprenal.00023.2012

Cited by 41 publications

(46 citation statements)

References 60 publications

(79 reference statements)

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“…Our results are in line with studies in mouse sepsis models, which also show marked reductions in occludin and claudin 5 levels (36,37). Studies in septic mice have also shown decreased ZO-1 expression and disorganized patterning with greater fragmentation, similar to our findings in the zebrafish sepsis model (38). We also saw upregulation of claudin 2 expression, pore forming tight junction protein, known to be markedly upregulated in mouse polymicrobial sepsis models (37).…”

Section: Discussionsupporting

confidence: 91%

Development of a Zebrafish Sepsis Model for High-Throughput Drug Discovery

Philip

Wang

Mauro

et al. 2017

Mol Med

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Sepsis is a leading cause of death worldwide. Current treatment modalities remain largely supportive. Intervention strategies focused on inhibiting specific mediators of the inflammatory host response have been largely unsuccessful, a consequence of an inadequate understanding of the complexity and heterogeneity of the innate immune response. Moreover, the conventional drug-development pipeline is time-consuming and expensive, and the low success rates associated with cell-based screens underline the need for whole-organism screening strategies, especially for complex pathological processes. Here, we established a lipopolysaccharide (LPS)-induced zebrafish endotoxemia model, which exhibits the major hallmarks of human sepsis, including edema and tissue/organ damage, increased vascular permeability and vascular leakage accompanied by altered expression of cellular junction proteins, increased cytokine expression, immune cell activation and reactive oxygen species (ROS) production, reduced circulation and increased platelet aggregation. We tested the suitability of the model for phenotype-based drug screening using three primary readouts: mortality, vascular leakage and ROS production. Preliminary screening identified fasudil, a drug known to protect against vascular leakage in murine models, as a lead hit, thereby validating the utility of our model for sepsis drug screens. This zebrafish sepsis model has the potential to rapidly analyze sepsis-associated pathologies and cellular processes in the whole organism, as well as to screen and validate many compounds that can modify sepsis pathology in vivo.

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Section: Discussionsupporting

confidence: 91%

Development of a Zebrafish Sepsis Model for High-Throughput Drug Discovery

Philip

Wang

Mauro

et al. 2017

Mol Med

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“…In mice and other animal models, LPS induces AKI, which is accompanied by a robust inflammatory response including leukocyte infiltration (Wang et al, 2009;Zahedi et al, 2010;Eadon et al, 2012). Proximal tubular cells are thought to play a role in the interstitial leukocyte infiltration in kidneys because of their anatomic proximity and ability to produce proinflammatory mediators and chemotactic cytokines (Danoff, 1998;Wan et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Paclitaxel Ameliorates Lipopolysaccharide-Induced Kidney Injury by Binding Myeloid Differentiation Protein-2 to Block Toll-Like Receptor 4–Mediated Nuclear Factor-κB Activation and Cytokine Production

Zhang

Liu

et al. 2013

J Pharmacol Exp Ther

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Recent studies suggest that paclitaxel, an anticancer agent, may modulate the injury and inflammatory responses in normal tissues. However, the underlying mechanism is not fully understood. Here we have examined the effect of paclitaxel on lipopolysaccharide (LPS)-induced acute kidney injury (AKI) in mice and further studied the mechanism. At relatively low doses, paclitaxel protected against LPS-induced AKI and improved animal survival. The beneficial effects of paclitaxel were accompanied by the downregulation of tumor necrosis factor-a, interleukin-1, and interleukin-6 production. In cultured renal tubular HK-2 cells, paclitaxel decreased the DNA-binding activity of nuclear factor-kB (NF-kB) during LPS treatment, inhibited the degradation of the inhibitor of kB-a, and blocked the expression and activation of NF-kB p65. At the upstream level, paclitaxel reduced LPS-induced association of myeloid differentiation protein-2 (MD-2) with Toll-like receptor 4 (TLR4). In an in vitro assay, paclitaxel was shown to directly bind recombinant MD-2. The inhibitory effect of paclitaxel on NF-kB activation and cytokine expression disappeared in MD-2 knockdown cells, indicating that paclitaxel acts through MD-2. Collectively, these results suggest that paclitaxel may bind MD-2 to block MD-2/ TLR4 association during LPS treatment, resulting in the suppression of NF-kB activation and inhibition of proinflammatory cytokine production.

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“…33,34 Another possibility is paracellular back-leak due to alterations in the actin cytoskeleton and the disruption of tight junctions. 35 This leakage may occur only at the electrolyte level (i.e., water or sodium ions), because paracellular leakage of larger molecules, such as FITC-inulin and Lucifer yellow, was not observed. Using conditional KO mice (e.g., renal tubulespecific TLR4 KO mice) in combination with yet undeveloped advanced imaging techniques that enable the visualization of paracellular (or intracellular) ion leakage may more directly clarify the (molecular) mechanism.…”

Section: Discussionmentioning

confidence: 99%

Reduction of Tubular Flow Rate as a Mechanism of Oliguria in the Early Phase of Endotoxemia Revealed by Intravital Imaging

Nakano¹,

Doi

Kitamura

et al. 2015

Journal of the American Society of Nephrology

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Urine output is widely used as a criterion for the diagnosis of AKI. Although several potential mechanisms of septic AKI have been identified, regulation of urine flow after glomerular filtration has not been evaluated. This study evaluated changes in urine flow in mice with septic AKI. The intratubular urine flow rate was monitored in real time by intravital imaging using two-photon laser microscopy. The tubular flow rate, as measured by freely filtered dye (FITC-inulin or Lucifer yellow), time-dependently declined after LPS injection. At 2 hours, the tubular flow rate was slower in mice injected with LPS than in mice injected with saline, whereas BP and GFR were similar in the two groups. Importantly, fluorophore-conjugated LPS selectively accumulated in the proximal tubules that showed reduced tubular flow at 2 hours and luminal obstruction with cell swelling at 24 hours. Delipidation of LPS or deletion of Toll-like receptor 4 in mice abolished these effects, whereas neutralization of TNF-a had little effect on LPS-induced tubular flow retention. Rapid intravenous fluid resuscitation within 6 hours improved the tubular flow rate only when accompanied by the dilation of obstructed proximal tubules with accumulated LPS. These findings suggest that LPS reduces the intratubular urine flow rate during early phases of endotoxemia through a Toll-like receptor 4-dependent mechanism, and that the efficacy of fluid resuscitation may depend on the response of tubules with LPS accumulation.

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Endotoxemia alters tight junction gene and protein expression in the kidney

Cited by 41 publications

References 60 publications

Development of a Zebrafish Sepsis Model for High-Throughput Drug Discovery

Development of a Zebrafish Sepsis Model for High-Throughput Drug Discovery

Paclitaxel Ameliorates Lipopolysaccharide-Induced Kidney Injury by Binding Myeloid Differentiation Protein-2 to Block Toll-Like Receptor 4–Mediated Nuclear Factor-κB Activation and Cytokine Production

Reduction of Tubular Flow Rate as a Mechanism of Oliguria in the Early Phase of Endotoxemia Revealed by Intravital Imaging

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