scholarly journals Dexmedetomidine Alleviates Lipopolysaccharide-Induced Acute Kidney Injury by Inhibiting p75NTR-Mediated Oxidative Stress and Apoptosis

2020 ◽  
Vol 2020 ◽  
pp. 1-13 ◽  
Author(s):  
Zhe Wang ◽  
Jiali Wu ◽  
Zhaolan Hu ◽  
Cong Luo ◽  
Pengfei Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Renal Function ◽  
Epithelial Cell ◽  
Signaling Pathways ◽  
Caspase 3 ◽  
Kidney Injury ◽  
Tubular Epithelial Cell ◽  
Tunel Staining ◽  
Jnk Signaling

Oxidative stress and apoptosis play a key role in the pathogenesis of sepsis-associated acute kidney injury (AKI). Dexmedetomidine (DEX) may present renal protective effects in sepsis. Therefore, we studied antioxidant effects and the mechanism of DEX in an inflammatory proximal tubular epithelial cell model and lipopolysaccharide- (LPS-) induced AKI in mice. Methods. We assessed renal function (creatinine, urea nitrogen), histopathology, oxidative stress (malondialdehyde (MDA) and superoxide dismutase (SOD)), and apoptosis (TUNEL staining and Cleaved caspase-3) in mice. In vitro experiments including Cleaved caspase-3 and p75NTR/p38MAPK/JNK signaling pathways were evaluated using western blot. Reactive oxidative species (ROS) production and apoptosis were determined using flow cytometry. Results. DEX significantly improved renal function and kidney injury and also revert the substantially increased level of MDA concentrations as well as the reduction of the SOD enzyme activity found in LPS-induced AKI mice. In parallel, DEX treatment also reduced the apoptosis and Cleaved caspase-3 expression evoked by LPS. The expression of p75NTR was increased in kidney tissues of mice with AKI but decreased after treatment with DEX. In cultured human renal tubular epithelial cell line (HK-2 cells), DEX inhibited LPS-induced apoptosis and generation of ROS, but this was reversed by overexpression of p75NTR. Furthermore, pretreatment with DEX significantly downregulated phosphorylation of JNK and p38MAPK in LPS-stimulated HK-2 cells, and this effect was abolished by overexpression of p75NTR. Conclusion. DEX ameliorated AKI in mice with sepsis by partially reducing oxidative stress and apoptosis through regulation of p75NTR/p38MAPK/JNK signaling pathways.

scholarly journals A Novel Antioxidant Protects Against Contrast Medium-Induced Acute Kidney Injury in Rats

2020 ◽  
Vol 11 ◽  
Author(s):  
Shuo Huang ◽  
Yanyan Tang ◽  
Tianjun Liu ◽  
Ning Zhang ◽  
Xueyan Yang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Superoxide Dismutase ◽  
Renal Function ◽  
Cytochrome C ◽  
Caspase 3 ◽  
Mitochondrial Protein ◽  
Kidney Injury ◽  
High Efficient ◽  
Superoxide Dismutase 2

Many studies proposed that oxidative stress and apoptosis are key mechanisms in the pathogenesis of contrast-induced acute kidney injury (CI-AKI). Xylose-pyrogallol conjugate (XP) is an original effective antioxidant that showed decent antioxidant and anti-apoptosis effect before. Thus the therapeutic effect and mechanism of XP in preventing CI-AKI in the short and long term were investigated in this research. Renal function and histological grade were evaluated to determine the severity of renal injury. Kidney samples were then collected for the measurement of oxidative stress markers and the detection of apoptosis. Transmission electron microscopy (TEM) and western blot of mitochondrial protein were utilized for the analysis of the mitochondrial conditions. The results demonstrated that the CI-AKI rats caused a significant decrease in renal function accompanied by a remarkable increase in Malondialdehyde (MDA), bax, caspase-3, cytochrome c (Cyt C) level, TdT-mediated dUTP nick end labeling (TUNEL) positive apoptotic cells, and damaged mitochondria, while a decline in antioxidase activities and mitochondrial superoxide dismutase 2 (SOD2) expression compared with the control rats. However, when XP (50 or 100 or 200 mg/kg/day) was given orally for consecutive 7 days before CI-AKI modeling, XP (200 mg/kg) showed a better capability to restore renal dysfunction, histopathological appearance, the level of apoptosis, mitochondrial damage, oxidative stress, and fibrosis generation without interference in computed tomographic imaging. Our study indicated that antioxidant XP played a nephroprotective role probably via antiapoptotic and antioxidant mechanisms. Besides, XP may regulate the mitochondria pathway via decreasing the ratio of bax/bcl-2, inhibiting caspase-3 expression, cytochrome c release, and superoxide dismutase 2 activity. Overall, XP as a high-efficient antioxidant may have the potentials to prevent CI-AKI.

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 MDM2 prevents spontaneous tubular epithelial cell death and acute kidney injury

2016 ◽  
Vol 7 (11) ◽  
pp. e2482-e2482 ◽  
Author(s):  
Dana Thomasova ◽  
Martrez Ebrahim ◽  
Kristina Fleckinger ◽  
Moying Li ◽  
Jakob Molnar ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Cell Death ◽  
Epithelial Cell ◽  
Kidney Injury ◽  
Tubular Epithelial Cell ◽  
Epithelial Cell Death

scholarly journals Pathophysiological role of different tubular epithelial cell death modes in acute kidney injury

2015 ◽  
Vol 8 (5) ◽  
pp. 548-559 ◽  
Author(s):  
Sandra M. Sancho-Martínez ◽  
José M. López-Novoa ◽  
Francisco J. López-Hernández
Keyword(s):  
Acute Kidney Injury ◽  
Cell Death ◽  
Epithelial Cell ◽  
Kidney Injury ◽  
Tubular Epithelial Cell ◽  
Pathophysiological Role ◽  
Epithelial Cell Death

scholarly journals SIRT1/3 Activation by Resveratrol Attenuates Acute Kidney Injury in a Septic Rat Model

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Siqi Xu ◽  
Youguang Gao ◽  
Qin Zhang ◽  
Siwei Wei ◽  
Zhongqing Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Survival Time ◽  
Rat Model ◽  
Cecal Ligation ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Tubular Epithelial Cell ◽  
Multiple Organ ◽  
Organ Systems

Sepsis often results in damage to multiple organ systems, possibly due to severe mitochondrial dysfunction. Two members of the sirtuin family, SIRT1 and SIRT3, have been implicated in the reversal of mitochondrial damage. The aim of this study was to determine the role of SIRT1/3 in acute kidney injury (AKI) following sepsis in a septic rat model. After drug pretreatment and cecal ligation and puncture (CLP) model reproduction in the rats, we performed survival time evaluation and kidney tissue extraction and renal tubular epithelial cell (RTEC) isolation. We observed reduced SIRT1/3 activity, elevated acetylated SOD2 (ac-SOD2) levels and oxidative stress, and damaged mitochondria in RTECs following sepsis. Treatment with resveratrol (RSV), a chemical SIRT1 activator, effectively restored SIRT1/3 activity, reduced acetylated SOD2 levels, ameliorated oxidative stress and mitochondrial function of RTECs, and prolonged survival time. However, the beneficial effects of RSV were greatly abrogated by Ex527, a selective inhibitor of SIRT1. These results suggest a therapeutic role for SIRT1 in the reversal of AKI in septic rat, which may rely on SIRT3-mediated deacetylation of SOD2. SIRT1/3 activation could therefore be a promising therapeutic strategy to treat sepsis-associated AKI.

CXCR4-overexpressing bone marrow-derived mesenchymal stem cells improve repair of acute kidney injury

2013 ◽  
Vol 305 (7) ◽  
pp. F1064-F1073 ◽  
Author(s):  
Nanmei Liu ◽  
Andreas Patzak ◽  
Jinyuan Zhang
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Acute Kidney Injury ◽  
Cell Death ◽  
Mesenchymal Stem Cells ◽  
Renal Function ◽  
Caspase 3 ◽  
Kidney Injury ◽  
Nuclear Antigen ◽  
Tubular Cells

Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) can repair acute kidney injury (AKI), but with limited effect. We test the hypothesis that CXCR4 overexpression improves the repair ability of BMSCs and that this is related to increased homing of BMSCs and increased release of cytokines. Hypoxia/reoxygenation-pretreated renal tubular epithelial cells (HR-RTECs) were used. BMSCs, null-BMSCs, and CXCR4-BMSCs were cocultured with HR-RTECs. The number of migrating BMSCs was counted. Proliferating cell nuclear antigen (PCNA) expression, cell death, and expressions of cleaved caspase-3 and Bcl-2 in cocultured HR-RTECs were measured. Cytokeratin 18 (CK18) expression and cytokine secretions of the BMSCs cultured with HR-RTEC supernatant were detected. BMSC homing, renal function, proliferation, and cell death of tubular cells were assayed in the AKI mouse model. CXCR4-BMSCs showed a remarkable expression of CXCR4. Stromal cell-derived factor-1 in the HR-RTEC supernatant was increased. Migration of BMSCs was CXCR4-dependent. Proportions of CK18+ cells in BMSCs, null-BMSCs, and CXCR4-BMSCs showed no difference. However, CXCR4 overexpression in BMSCs stimulated secretion of bone morphogenetic protein-7, hepatocyte growth factor, and interleukin 10. The neutralizing anti-CXCR4 antibody AMD3100 abolished this. In cocultured HR-RTECs the proportions of PCNA+ cells and Bcl-2 expression were enhanced; however, the proportion of annexin V+ cells and expression of cleaved caspase-3 were reduced. The in vivo study showed increased homing of CXCR4-BMSCs in kidneys, which was associated with improved renal function, reduced acute tubular necrosis scoring, accelerated mitogenic response of tubular cells, and reduced tubular cell death. The enhanced homing and paracrine actions of BMSCs with CXCR4 overexpression suggest beneficial effects of such cells in BMSC-based therapy for AKI.

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