scholarly journals The Mechanisms of the Herbal Components of CRSAS on HK-2 Cells in a Hypoxia/Reoxygenation Model Based on Network Pharmacology

2020 ◽  
Vol 2020 ◽  
pp. 1-10 ◽  
Author(s):  
Naijing Ye ◽  
Dengpiao Xie ◽  
Bing Yang ◽  
Mingquan Li
Keyword(s):  
Acute Kidney Injury ◽  
Cell Apoptosis ◽  
Salvia Miltiorrhiza ◽  
Kidney Injury ◽  
Cell Counting ◽  
Network Pharmacology ◽  
Renal Tubular ◽  
Carboxyfluorescein Succinimidyl Ester ◽  
Great Burden ◽  
Hypoxia Reoxygenation

Background. Acute kidney injury is a global problem, which brings a great burden to the society and family. The component of rhubarb, Salvia miltiorrhiza, Astragalus membranaceus, and safflower (CRSAS) has been proved as an useful agent to treat acute kidney injury (AKI) patients in China. Objective. To assess the effect of CRSAS on human renal tubular epithelial cells (HK-2) after the hypoxia/reoxygenation (H/R) and investigate the potential mechanisms. Methods. Network pharmacology was used to predict the potential pathways shared by CRSAS and AKI. Cell counting kit-8 (CCK-8) was used to assess the HK-2 vitality. Apoptosis of HK-2 cells was detected by carboxyfluorescein succinimidyl ester/propidium iodide (CFSF/PI) staining. Expression of GRP78, CHOP, caspase-3, and Bax was detected by western blot and quantitative real-time RT-PCR. Result. CRSAS and AKI shared the endoplasmic reticulum stress (ERS) pathway based on network pharmacology analysis. CRSAS increases the vitality of HK-2 cells and reduces the apoptosis of HK-2 cells induced by H/R injury. The expression of GRP78 and CHOP in CRSAS groups was lower than that of control groups. Conclusions. H/R can induce HK-2 cell apoptosis and ERS. CRSAS can reduce HK-2 cell apoptosis by inhibiting the ERS. Therefore, CRSAS might be able to treat kidney disease due to I/R injury. Animal experiment should be done to further prove our finding.

miR-30e-5p regulates autophagy and apoptosis by targeting Beclin1 involved in contrast-induced acute kidney injury

2021 ◽  
Vol 28 ◽  
Author(s):  
Xiaoqin Liu ◽  
Qingzhao Li ◽  
Lixin Sun ◽  
Limei Chen ◽  
Yue Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Kidney Injury ◽  
Cell Apoptosis ◽  
Cell Injury ◽  
Cell Model ◽  
Kidney Injury ◽  
Cell Vitality ◽  
A Cell ◽  
Renal Tubular ◽  
Induced Apoptosis

Aims: This study aims to verify if miR-30e-5p targets Beclin1 (BECN1), a key regulator of autophagy, and investigate the function of miR-30e-5p and Beclin1 through mediating autophagy and apoptosis in contrast-induced acute kidney injury (CI-AKI). Methods: Human renal tubular epithelial HK-2 cells were treated with Urografin to construct a cell model of CI-AKI. Real-time reverse transcription–polymerase chain reaction was used to detect gene expression. The dual-luciferase reporting assay and endogenous validation were used to verify targeting and regulating function. The expressions of protein were detected using Western blot. Cell proliferation was detected using methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay. Cell apoptosis was detected using terminal-deoxynucleoitidyl transferase mediated nick end labeling assay, and autophagy was detected using transmission electron microscopy. Results: HK-2 cells exposed to Urografin for 2 h induced a significant increase in miR-30e-5p. miR-30e-5p had a targeting effect on Beclin1. Moreover, Urografin exposure can enhance cell apoptosis by increasing caspase 3 gene expression and inhibiting autophagy, which was induced by decreased Beclin1 expression regulated by miR-30e-5p, thereby resulting in renal cell injury. Downregulation of miR-30e-5p or upregulation of Beclin1 restored cell vitality by promoting autophagy and suppressing apoptosis in Urografin-treated cells. Conclusions: Urografin increased the expression of miR-30e-5p in HK-2 cells and thus decreased Beclin1 levels to inhibit autophagy, but induced apoptosis, which may be the mechanism for CI-AKI.

scholarly journals Class IIa HDAC inhibitor TMP195 alleviates lipopolysaccharide-induced acute kidney injury

2020 ◽  
Vol 319 (6) ◽  
pp. F1015-F1026
Author(s):  
Wei Zhang ◽  
Yinjie Guan ◽  
George Bayliss ◽  
Shougang Zhuang
Keyword(s):  
Acute Kidney Injury ◽  
Hdac Inhibitor ◽  
Cell Apoptosis ◽  
Kidney Injury ◽  
Tubular Cell ◽  
Intercellular Adhesion Molecule ◽  
Renal Tubular Cell ◽  
Renoprotective Effect ◽  
Renal Tubular ◽  
Class Iia Hdacs

Sepsis-associated acute kidney injury (SA-AKI) is associated with high mortality rates, but clinicians lack effective treatments except supportive care or renal replacement therapies. Recently, histone deacetylase (HDAC) inhibitors have been recognized as potential treatments for acute kidney injury and sepsis in animal models; however, the adverse effect generated by the use of pan inhibitors of HDACs may limit their application in people. In the present study, we explored the possible renoprotective effect of a selective class IIa HDAC inhibitor, TMP195, in a murine model of SA-AKI induced by lipopolysaccharide (LPS). Administration of TMP195 significantly reduced increased serum creatinine and blood urea nitrogen levels and renal damage induced by LPS; this was coincident with reduced expression of HDAC4, a major isoform of class IIa HDACs, and elevated histone H3 acetylation. TMP195 treatment following LPS exposure also reduced renal tubular cell apoptosis and attenuated renal expression of neutrophil gelatinase-associated lipocalin and kidney injury molecule-1, two biomarkers of tubular injury. Moreover, LPS exposure resulted in increased expression of BAX and cleaved caspase-3 and decreased expression of Bcl-2 and bone morphogenetic protein-7 in vivo and in vitro; TMP195 treatment reversed these responses. Finally, TMP195 inhibited LPS-induced upregulation of multiple proinflammatory cytokines/chemokines, including intercellular adhesion molecule-1, monocyte chemoattractant protein-1, tumor necrosis factor-α, and interleukin-1β, and accumulation of inflammatory cells in the injured kidney. Collectively, these data indicate that TMP195 has a powerful renoprotective effect in SA-AKI by mitigating renal tubular cell apoptosis and inflammation and suggest that targeting class IIa HDACs might be a novel therapeutic strategy for the treatment of SA-AKI that avoids the unintended adverse effects of a pan-HDAC inhibitor.

scholarly journals p53-cyclophilin D mediates renal tubular cell apoptosis in ischemia-reperfusion-induced acute kidney injury

2019 ◽  
Vol 317 (5) ◽  
pp. F1311-F1317 ◽  
Author(s):  
Huan Yang ◽  
Ruizhao Li ◽  
Li Zhang ◽  
Shu Zhang ◽  
Wei Dong ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Cell Death ◽  
Cell Apoptosis ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Tubular Cell ◽  
Renal Tubular Cell ◽  
Cyclophilin D ◽  
Mptp Opening ◽  
Renal Tubular

Ischemia-reperfusion (I/R)-induced acute kidney injury (I/R-AKI) favors mitochondrial permeability transition pore (mPTP) opening and subsequent cell death. Cyclophilin D (CypD) is an essential component of the mPTP, and recent findings have implicated the p53-CypD complex in cell death. To evaluate the role of p53-CypD after I/R-AKI, we tested the hypothesis that the p53-CypD complex mediates renal tubular cell apoptosis in I/R-AKI via mPTP opening. Expression of p53 and cleaved caspase-3 was significantly increased in rats subjected to I/R-AKI compared with normal controls and sham-operated controls. The underlying mechanisms were determined using an in vitro model of ATP depletion. Inhibition of mPTP opening using the CypD inhibitor cyclosporin A or siRNA for p53 in ATP-depleted HK-2 cells prevented mitochondrial membrane depolarization and reduced apoptosis. Furthermore, p53 bound to CypD in ATP-depleted HK-2 cells. These results suggest that the p53-CypD complex mediates renal tubular cell apoptosis in I/R-AKI via mPTP opening.

scholarly journals USP10 alleviates sepsis-induced acute kidney injury by regulating Sirt6-mediated Nrf2/ARE signaling pathway

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Fei Gao ◽  
Mingjiang Qian ◽  
Guoyue Liu ◽  
Wanping Ao ◽  
Dahua Dai ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Epithelial Cell ◽  
Western Blot ◽  
Cell Apoptosis ◽  
Cell Injury ◽  
Kidney Injury ◽  
Tubular Epithelial Cell ◽  
Renal Tubular Epithelial Cell ◽  
Renal Tubular

Abstract Background Severe sepsis, a major health problem worldwide, has become one of the leading causes of death in ICU patients. Further study on the pathogenesis and treatment of acute kidney injury (AKI) is of great significance to reduce high mortality rate of sepsis. In this study, the mechanism by which ubiquitin specific peptidase 10 (USP10) reduces sepsis-induced AKI was investigated. Ligation and perforation of cecum (CLP) was employed to establish C57BL/6 mouse models of sepsis. Hematoxylin-eosin (H&E) staining was performed to detect renal injury. The concentrations of serum creatinine (Cr), urea nitrogen (BUN) and cystatin C (Cys C) were determined using a QuantiChrom™ Urea Assay kit. RT-qPCR and western blot were conducted to assess the USP10 expression level. DHE staining was used to detect reactive oxygen species (ROS) levels. H2O2, MDA and SOD levels were assessed using corresponding colorimetric kits. Western blot was used to examine the expression levels of Bcl-2, Bax, cleaved caspase-3, Sirt6, Nrf2 and HO-1. MTT assay was used to determine cell viability, whereas TUNEL staining and flow cytometry were used to assess cell apoptosis. Results In this study, we found that USP10 was decreased in CLP-induced mouse renal tissues. We identified that USP10 alleviated renal dysfunction induced by CLP. Moreover, USP10 was found to reduce oxidative stress, and abated LPS-induced renal tubular epithelial cell injury and apoptosis. Finally, we discovered that USP10 promoted activation of the NRF2/HO-1 pathway through SIRT6 and attenuated LPS-induced renal tubular epithelial cell injury. Conclusions This study found that USP10 activates the NRF2/ARE signaling through SIRT6. USP10 alleviates sepsis-induced renal dysfunction and reduces renal tubular epithelial cell apoptosis and oxidative stress.

scholarly journals Quercetin as a potential treatment for COVID-19-induced acute kidney injury: Based on network pharmacology and molecular docking study

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0245209
Author(s):  
Yue-Yu Gu ◽  
Min Zhang ◽  
Huan Cen ◽  
Yi-Fan Wu ◽  
Zhaoyu Lu ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Molecular Docking ◽  
Signaling Pathways ◽  
Cell Apoptosis ◽  
Active Sites ◽  
Inflammatory Cell ◽  
Specific Treatment ◽  
Kidney Injury ◽  
Network Pharmacology ◽  
Molecular Docking Study

Kidneys are one of the targets for SARS-CoV-2, it is reported that up to 36% of patients with SARS-CoV-2 infection would develop into acute kidney injury (AKI). AKI is associated with high mortality in the clinical setting and contributes to the transition of AKI to chronic kidney disease (CKD). Up to date, the underlying mechanisms are obscure and there is no effective and specific treatment for COVID-19-induced AKI. In the present study, we investigated the mechanisms and interactions between Quercetin and SARS-CoV-2 targets proteins by using network pharmacology and molecular docking. The renal protective effects of Quercetin on COVID-19-induced AKI may be associated with the blockade of the activation of inflammatory, cell apoptosis-related signaling pathways. Quercetin may also serve as SARS-CoV-2 inhibitor by binding with the active sites of SARS-CoV-2 main protease 3CL and ACE2, therefore suppressing the functions of the proteins to cut the viral life cycle. In conclusion, Quercetin may be a novel therapeutic agent for COVID-19-induced AKI. Inhibition of inflammatory, cell apoptosis-related signaling pathways may be the critical mechanisms by which Quercetin protects kidney from SARS-CoV-2 injury.

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