Lipopolysaccharide Mediates the Destruction of Intercellular Tight Junction among Renal Tubular Epithelial Cells via RhoT1/SMAD-4/JAM-3 Pathway

Zheng, Shixiang; Lin, Zhuoyong; Liu, Zhongwei; Liu, Yipeng; Wu, Wenwei

doi:10.7150/ijms.23786

Cited by 12 publications

(11 citation statements)

References 25 publications

(26 reference statements)

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“…However, to date, little progress has been achieved and the mechanisms inducing AKI during sepsis are still mysterious. In our previous study that aimed to look for the possible mechanisms of SAKI, we found out that the alteration of functional status and structure of TECs was critically related to the occurrence of SAKI [34,35]. These findings are consistent with the conclusions of previous studies focusing on AKI.…”

Section: Discussionsupporting

confidence: 89%

MiR-21-3p Plays a Crucial Role in Metabolism Alteration of Renal Tubular Epithelial Cells during Sepsis Associated Acute Kidney Injury via AKT/CDK2-FOXO1 Pathway

Lin

Liu

Wang

et al. 2019

BioMed Research International

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Objective. Sepsis and associated acute kidney injury (SAKI) are determined to be closely related to poor prognosis. Because the metabolic alterations of tubular epithelial cells (TECs) are crucial for the occurrence and development of SAKI, we carried out this present study to identify the metabolism changes of TECs during SAKI and relevant mechanisms. Methods. Rat SAKI model and rat tubular epithelial cell line were used in our study. ELISA was used to determine the serum cytokines levels. Protein expressions were examined with Western-Blotting and the transcriptions of RNAs were determined with qRT-PCR. ADP/ATP assay and Oil Red O staining were used to examine the energy and lipid metabolism, respectively. Dual-luciferase reporter assay was carried out to determine the interactions between miRNA and specific proteins. Cell cycle arrest and apoptosis were determined with flow cytometry. Results. Sepsis and AKI were induced 12 h after CLP. Energy and lipid metabolism reduced significantly while FOXO1 levels increased remarkably in TECs during SAKI. The expressions of both AKT and CDK2 and the transcriptions of relevant mRNAs reduced significantly in TECs during SAKI while miR-21-3p expression increased remarkably. Both AKT and CDK2 were determined as the direct targets of miR-21-3p. Furthermore, by in vitro experiments, it was demonstrated that FOXO1 levels were regulated by miR-21-3p in TECs via AKT/CDK2 and AKT/CDK2-FOXO1 pathway was crucial in the regulations of miR-21-3p on lipid metabolism, cell cycle arrest, and apoptosis of TECs. Conclusions. MiR-21-3p mediates metabolism and cell fate alterations of TECs via manipulating AKT/CDK2-FOXO1 pathway, and that is crucial in the regulation of energy metabolism of TECs during SAKI.

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Section: Discussionsupporting

confidence: 89%

MiR-21-3p Plays a Crucial Role in Metabolism Alteration of Renal Tubular Epithelial Cells during Sepsis Associated Acute Kidney Injury via AKT/CDK2-FOXO1 Pathway

Lin

Liu

Wang

et al. 2019

BioMed Research International

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“…TECs act as one of the most vulnerable inherent cells in the kidney during sepsis. It has been demonstrated that when stimulated with sepsis-associated circulatory factors such as LPS and HMGB1, TECs will undergo a series of morphological and functional abnormalities which become the pivotal causes of AKI [ 27 – 29 ]. Moreover, our previous study has demonstrated that the miR-21a-3p content was increased in TECs, while miR-21a-3p mediates metabolism and cell fate alteration of TECs via manipulating the AKT/CDK2-FOXO1 pathway during SAKI [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Nrp-1 Mediated Plasmatic Ago2 Binding miR-21a-3p Internalization: A Novel Mechanism for miR-21a-3p Accumulation in Renal Tubular Epithelial Cells during Sepsis

Zou

Lin

Yang

et al. 2020

BioMed Research International

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The mechanism underlying sepsis-associated acute kidney injury (SAKI), which is an independent risk factor for sepsis-associated death, is unclear. A previous study indicates that during sepsis miR-21a-3p accumulates in renal tubular epithelial cells (TECs) as the mediator of inflammation and mediates TEC malfunction by manipulating its metabolism. However, the specific mechanism responsible for the accumulation of miR-21a-3p in TECs during sepsis is unrevealed. In this study, a cecal ligation and puncture- (CLP-) induced sepsis rat model and rat TEC line were used to elucidate the mechanism. Firstly, miR-21a-3p and Ago2 levels were found out to increase in both plasma and TECs during sepsis, and the increase of intracellular Ago2 and miR-21a-3p could be mitigated when Ago2 was either inactivated or downregulated in septic plasma. Moreover, membrane Nrp-1 expression of TECs was increased significantly during sepsis and Nrp-1 knockdown also mitigated the rise of both the intracellular Ago2 and miR-21a-3p levels in TECs incubated with septic plasma. Furthermore, it was revealed that Ago2 can be internalized by TECs mediated with Nrp-1 and this process had no effect on the intracellular content of miR-21a-3p. Both Ago2 and miR-21a-3p could bind to TECs derived Nrp-1 directly. Finally, it was determined that miR-21a-3p was internalized by TECs via Nrp-1 and Ago2 facilitated this process. Taken together, it can be concluded from our results that Ago2 binding miR-21a-3p from septic plasma can be actively internalized by TECs via Nrp-1 mediated cell internalization, and this mechanism is crucial for the rise of intracellular miR-21a-3p content of TECs during sepsis. These findings will improve our understanding of the mechanisms underlying SAKI and aid in developing novel therapeutic strategies.

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“…Adherens junctions (AJ), represented by cadherin, and tight junctions (TJ), represented by occluding, are the main cell junctions involved in formation of barriers31, 32. Components of the barrier become damaged during sepsis and normal intercellular junctions are destroyed, which leads to increased barrier permeability29, 30, 33. Subsequently, proteins or liquids leak out of the blood vessels into tissues, leading to edema and hypoproteinemia, which aggravate endotoxin shock34.…”

Section: Molecular Hydrogen Reduces the Physiological Barrier Dysfuncmentioning

confidence: 99%

“…Many studies have investigated how molecular hydrogen alleviates the physiological barrier damage caused by sepsis, including protective effects on vascular endothelial cells30, 35, 36, epithelial cells (e.g., alveoli and gastrointestinal epithelium)9, 11, 29, 37 and intercellular junctions9, 30, 33, 38, which are characterized by decreased permeability, increased transmembrane resistance, and regulation of expression and distribution of intercellular junction- related proteins.…”

Section: Molecular Hydrogen Reduces the Physiological Barrier Dysfuncmentioning

confidence: 99%

Recent Advances in Studies of Molecular Hydrogen against Sepsis

2019

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Sepsis is a syndrome comprised of a series of life-threatening organ dysfunctions caused by a maladjusted body response to infection with no effective treatment. Molecular hydrogen is a new type of antioxidant with strong free radical scavenging ability, which has been demonstrated to be effective for treating various diseases, such as infection, trauma, poisoning, organ ischemia-reperfusion, metabolic diseases, and tumors. Molecular hydrogen exerts multiple biological effects involving anti-inflammation, anti-oxidation, anti-apoptosis, anti-shock, and autophagy regulation, which may attenuate the organ and barrier damage caused by sepsis. However, the underlying molecular mechanisms remain elusive, but are likely related to the signaling pathways involved. This review focuses on the research progress and potential mechanisms of molecular hydrogen against sepsis to provide a theoretical basis for clinical treatment.

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Lipopolysaccharide Mediates the Destruction of Intercellular Tight Junction among Renal Tubular Epithelial Cells via RhoT1/SMAD-4/JAM-3 Pathway

Cited by 12 publications

References 25 publications

MiR-21-3p Plays a Crucial Role in Metabolism Alteration of Renal Tubular Epithelial Cells during Sepsis Associated Acute Kidney Injury via AKT/CDK2-FOXO1 Pathway

MiR-21-3p Plays a Crucial Role in Metabolism Alteration of Renal Tubular Epithelial Cells during Sepsis Associated Acute Kidney Injury via AKT/CDK2-FOXO1 Pathway

Nrp-1 Mediated Plasmatic Ago2 Binding miR-21a-3p Internalization: A Novel Mechanism for miR-21a-3p Accumulation in Renal Tubular Epithelial Cells during Sepsis

Recent Advances in Studies of Molecular Hydrogen against Sepsis

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