scholarly journals HO-1/PINK1 Regulated Mitochondrial Fusion/Fission to Inhibit Pyroptosis and Attenuate Septic Acute Kidney Injury

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Hai-Bo Li ◽  
Xi-Zhe Zhang ◽  
Yi Sun ◽  
Qi Zhou ◽  
Jian-Nan Song ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Renal Function ◽  
Inflammatory Response ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Endotoxic Shock ◽  
Kidney Injury ◽  
Treated Group ◽  
Mitochondrial Fusion

Background. Endotoxin-associated acute kidney injury (AKI), a disease characterized by marked oxidative stress and inflammation disease, is a major cause of mortality in critically ill patients. Mitochondrial fission and pyroptosis often occur in AKI. However, the underlying biological pathways involved in endotoxin AKI remain poorly understood, especially those related to mitochondrial dynamics equilibrium disregulation and pyroptosis. Previous studies suggest that heme oxygenase- (HO-) 1 confers cytoprotection against AKI during endotoxic shock, and PTEN-induced putative kinase 1 (PINK1) takes part in mitochondrial dysfunction. Thus, in this study, we examine the roles of HO-1/PINK1 in maintaining the dynamic process of mitochondrial fusion/fission to inhibit pyroptosis and mitigate acute kidney injury in rats exposed to endotoxin. Methods. An endotoxin-associated AKI model induced by lipopolysaccharide (LPS) was used in our study. Wild-type (WT) rats and PINK1 knockout (PINK1KO) rats, respectively, were divided into four groups: the control, LPS, Znpp+LPS, and Hemin+LPS groups. Rats were sacrificed 6 h after intraperitoneal injecting LPS to assess renal function, oxidative stress, and inflammation by plasma. Mitochondrial dynamics, morphology, and pyroptosis were evaluated by histological examinations. Results. In the rats with LPS-induced endotoxemia, the expression of HO-1 and PINK1 were upregulated at both mRNA and protein levels. These rats also exhibited inflammatory response, oxidative stress, mitochondrial fission, pyroptosis, and decreased renal function. After upregulating HO-1 in normal rats, pyroptosis was inhibited; mitochondrial fission and inflammatory response to oxidative stress were decreased; and the renal function was improved. The effects were reversed by adding Znpp (a type of HO-1 inhibitor). Finally, after PINK1 knockout, there is no statistical difference in the LPS-treated group and Hemin or Znpp pretreated group. Conclusions. HO-1 inhibits inflammation response and oxidative stress and regulates mitochondria fusion/fission to inhibit pyroptosis, which can alleviate endotoxin-induced AKI by PINK1.

scholarly journals T-2 Toxin-Induced Oxidative Stress Leads to Imbalance of Mitochondrial Fission and Fusion to Activate Cellular Apoptosis in the Human Liver 7702 Cell Line

Toxins ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 43 ◽  
Author(s):  
Junhua Yang ◽  
Wenbo Guo ◽  
Jianhua Wang ◽  
Xianli Yang ◽  
Zhiqi Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Apoptosis ◽  
Human Liver ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Mitochondrial Fusion ◽  
Mitochondrial Dynamic ◽  
Normal Human Liver ◽  
Induced Apoptosis

T-2 toxin, as a highly toxic mycotoxin to humans and animals, induces oxidative stress and apoptosis in various cells and tissues. Apoptosis and mitochondrial fusion/fission are two tightly interconnected processes that are crucial for maintaining physiological homeostasis. However, the role of mitochondrial fusion/fission in apoptosis of T-2 toxin remains unknown. Hence, we aimed to explore the putative role of mitochondrial fusion/fission on T-2 toxin induced apoptosis in normal human liver (HL-7702) cells. T-2 toxin treatment (0, 0.1, 1.0, or 10 μg/L) for 24 h caused decreased cell viability and ATP concentration and increased production of (ROS), as seen by a loss of mitochondrial membrane potential (∆Ψm) and increase in mitochondrial fragmentation. Subsequently, the mitochondrial dynamic imbalance was activated, evidenced by a dose-dependent decrease and increase in the protein expression of mitochondrial fusion (OPA1, Mfn1, and Mfn2) and fission (Drp1 and Fis1), respectively. Furthermore, the T-2 toxin promoted the release of cytochrome c from mitochondria to cytoplasm and induced cell apoptosis triggered by upregulation of Bax and Bax/Bcl-2 ratios, and further activated the caspase pathways. Taken together, these results indicate that altered mitochondrial dynamics induced by oxidative stress with T-2 toxin exposure likely contribute to mitochondrial injury and HL-7702 cell apoptosis.

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 Angiotensin (1-7) Attenuates Sepsis-Induced Acute Kidney Injury by Regulating the NF-κB Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Ying Zhu ◽  
Daliang Xu ◽  
Fang Deng ◽  
Yonglin Yan ◽  
Jian Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Inflammatory Response ◽  
Cystatin C ◽  
Kidney Injury ◽  
Serum Levels ◽  
Control Group ◽  
Protective Mechanism ◽  
Ang Ii ◽  
Urea Nitrogen

This study explores the protective mechanism of angiotensin (1-7) [Ang-(1-7)] on kidneys by examining its effects on renal histomorphology, inflammatory response, oxidative stress, and NF-κB signaling in mice suffering from sepsis-induced acute kidney injury. A sepsis-induced acute kidney injury mouse model was established by intracervically injecting lipopolysaccharides (LPS group), followed by the administration of Ang-(1-7) [LPS + Ang-(1-7) group]. The serum levels of urea nitrogen, creatinine and cystatin. c were measured with an automatic biochemical analyzer, and changes in proinflammatory cytokines and angiotensin II (Ang II) in the serum and kidneys were quantified by enzyme-linked immunosorbent assays. Changes in oxidative stress indices in the renal cortex were detected by colorimetry. The localization of Ang II in kidneys was examined by immunohistochemistry. Western blotting was used to examine phosphorylated NF-κB-p65 and IκBα levels in kidneys. Compared with the control group, the serum levels of urea nitrogen, creatinine and cystatin. c were increased, whereas the levels of Ang II, TNFα, IL-1β, IL-6, and malondialdehyde (mda) were increased significantly. The levels of Ang II and phosphorylated NF-κB-p65 were elevated in kidneys, whereas the levels of superoxide dismutase (sod), Total antioxidative capacity (TAOC), and inhibitor of NF-κB (IκBα) were reduced in the LPS group (p < 0.05). Pathological damage was also observed in kidneys of LPS-group mice. In Pearson correlation analysis, there was a positive correlation between Ang II and phosphorylated NF-κB-p65 levels, and a negative correlation between Ang II and IκBα levels (p < 0.05). After the application of Ang-(1-7), the levels of urea nitrogen, creatinine, cystatin. c, Ang II, TNFα, IL-1β, IL-6, and mda, as well as the expression of Ang II and phosphorylated NF-κB-p65 in kidneys of LPS + Ang-(1-7)-group mice, were lower than those in kidneys of LPS-group mice, but the levels of sod, TAOC, and IκBα were higher than those of LPS-group mice (p < 0.05). Pathological changes were less severe in mice of the LPS + Ang-(1-7) group. Overall, Ang-(1-7) can decrease the Ang II level, inhibit NF-κB signaling, reduce the inflammatory response, decrease oxidative stress, and mitigate sepsis-associated acute kidney injury.

scholarly journals D-Limonene Alleviates Acute Kidney Injury Following Gentamicin Administration in Rats: Role of NF-κB Pathway, Mitochondrial Apoptosis, Oxidative Stress, and PCNA

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Esmaeel Babaeenezhad ◽  
Forouzan Hadipour Moradi ◽  
Sobhan Rahimi Monfared ◽  
Mohammad Davood Fattahi ◽  
Maryam Nasri ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Treated Group ◽  
Control Group ◽  
Myeloperoxidase Activity ◽  
Protective Effects ◽  
Mitochondrial Apoptosis ◽  
Protein Expressions ◽  
Apoptosis And Inflammation

Clinical application of gentamicin (GM) is well known to be associated with the development of acute kidney injury (AKI). This study was the first to investigate the possible protective effects of D-limonene (D-lim) on AKI following GM administration in rats. 32 rats arranged in four groups ( n = 8 ): (1) the control group received saline intraperitoneally (0.5 ml/day) and orally (0.5 ml/day), (2) the D-lim group received D-lim (100 mg/kg) orally and saline (0.5 ml/day) intraperitoneally, (3) the GM group received GM (100 mg/kg/day) intraperitoneally and saline (0.5 ml/day) orally, and (4) the treated group received intraperitoneal GM (100 mg/kg) and oral D-lim (100 mg/kg). All treatments were performed daily for 12 consecutive days. Results revealed that D-lim ameliorated GM-induced AKI, oxidative stress, mitochondrial apoptosis, and inflammation. D-lim showed nephroprotective effects as reflected by the decrease in serum urea and creatinine and improvement of renal histopathological changes. D-lim alleviated GM-induced oxidative stress by increasing the activities of renal catalase, serum and renal glutathione peroxidase, and renal superoxide dismutase and decreasing renal malondialdehyde and serum nitric oxide levels. Intriguingly, D-lim suppressed mitochondrial apoptosis by considerably downregulating Bax and caspase-3 (Casp-3) mRNA and protein expressions and markedly enhancing Bcl2 mRNA and protein expressions. Furthermore, D-lim significantly decreases GM-induced inflammatory response through downregulation of NF-κB, IL-6, and TNF-α mRNA and/or protein expressions and decrease in renal myeloperoxidase activity. Finally, D-lim remarkably downregulated PCNA protein expression in the treated group compared with the GM group. In brief, this study showed that D-lim alleviated AKI following GM administration in rats, partially through its antioxidant, anti-inflammatory, and antiapoptotic activities as well as downregulation of PCNA expression.

scholarly journals 5-HT1F receptor regulates mitochondrial homeostasis and its loss potentiates acute kidney injury and impairs renal recovery

2018 ◽  
Vol 315 (4) ◽  
pp. F1119-F1128 ◽  
Author(s):  
Whitney S. Gibbs ◽  
Justin B. Collier ◽  
Morgan Morris ◽  
Craig C. Beeson ◽  
Judit Megyesi ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Renal Function ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Kidney Injury ◽  
Renal Recovery ◽  
Tubular Injury ◽  
Mitochondrial Homeostasis ◽  
Mitochondrial Dna Copy Number ◽  
Proximal Tubular

Our laboratory previously reported that agonists of the 5-hydoxytryptamine 1F (5-HT1F) receptor induce renal mitochondrial biogenesis (MB) and that stimulation of the 5-HT1F receptor following ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) accelerated the recovery of renal function in mice. The goal of this study was to examine the contribution of the 5-HT1F receptor in the regulation of renal mitochondrial homeostasis and renal function in naïve and injured mice. Although 5-HT1F receptor knockout (KO) mice were healthy and fertile, and did not exhibit renal dysfunction, renal mitochondrial DNA copy number and mitochondrial fission gene expression increased at 10 wk of age. The 5-HT1F receptor KO mice exhibited greater proximal tubular injury and diminished renal recovery after I/R-induced AKI compared with wild-type mice. These findings were associated with persistent suppression of renal cortical MB and ATP levels after injury. In summary, the 5-HT1F receptor is a component of physiological MB regulation in the kidney, and its absence potentiates renal injury and impedes recovery.

scholarly journals Deletion of VDAC1 Hinders Recovery of Mitochondrial and Renal Functions After Acute Kidney Injury

Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 585 ◽  
Author(s):  
Grazyna Nowak ◽  
Judit Megyesi ◽  
William J. Craigen
Keyword(s):  
Acute Kidney Injury ◽  
Mitochondrial Function ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Kidney Injury ◽  
Atp Content ◽  
Respiratory Complexes ◽  
Kidney Morphology ◽  
Kidney Functions ◽  
Fof1 Atpase

Voltage-dependent anion channels (VDACs) constitute major transporters mediating bidirectional movement of solutes between cytoplasm and mitochondria. We aimed to determine if VDAC1 plays a role in recovery of mitochondrial and kidney functions after ischemia-induced acute kidney injury (AKI). Kidney function decreased after ischemia and recovered in wild-type (WT), but not in VDAC1-deficient mice. Mitochondrial maximum respiration, activities of respiratory complexes and FoF1-ATPase, and ATP content in renal cortex decreased after ischemia and recovered in WT mice. VDAC1 deletion reduced respiration and ATP content in non-injured kidneys. Further, VDAC1 deletion blocked return of activities of respiratory complexes and FoF1-ATPase, and recovery of respiration and ATP content after ischemia. Deletion of VDAC1 exacerbated ischemia-induced mitochondrial fission, but did not aggravate morphological damage to proximal tubules after ischemia. However, VDAC1 deficiency impaired recovery of kidney morphology and increased renal interstitial collagen accumulation. Thus, our data show a novel role for VDAC1 in regulating renal mitochondrial dynamics and recovery of mitochondrial function and ATP levels after AKI. We conclude that the presence of VDAC1 (1) stimulates capacity of renal mitochondria for respiration and ATP production, (2) reduces mitochondrial fission, (3) promotes recovery of mitochondrial function and dynamics, renal morphology, and kidney functions, and (4) increases survival after AKI.

P0525ROLE OF NADPH OXIDASE 4 IN ACUTE KIDNEY INJURY ASSOCIATED TO MASSIVE INTRAVASCULAR HEMOLYSIS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Cristina García Caballero ◽  
Melania Guerrero Hue ◽  
Alejandra Palomino Antolín ◽  
Matilde Cabanillas ◽  
Cristina Vazquez Carballo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Renal Function ◽  
Renal Damage ◽  
Kidney Injury ◽  
Tubular Injury ◽  
Wild Type ◽  
Intravascular Hemolysis ◽  
Nadph Oxidase 4

Abstract Background and Aims Massive intravascular hemolysis is a common condition of several pathologies. It is associated with acute kidney injury (AKI) and progressive impairment of renal function. In this context, free hemoglobin (Hb) can exert harmful effects by accumulating in the kidney, where induces oxidative stress and it becomes cytotoxic. NADPH oxidase 4 (Nox4) is the principal source of reactive oxygen species (ROS) in the kidney. Nox4 is mostly expressed in proximal tubular cells with lower levels in glomerulus. The role of Nox4 in renal damage is not clear, with studies reporting beneficial or deleterious actions depending of the environmental conditions. For that reason we aimed to investigate the role of Nox4 in massive intravascular hemolysis-associated AKI. Method To study the role of Nox4 in AKI caused by massive intravascular hemolysis, we performed an experimental model of intravascular hemolysis by intraperitoneal injection of phenylhydrazine (200 mg/kg) in wild type (Nox4+/+) and Nox4 knockout mice (Nox4-/-). Mice were sacrificed 24 and 72 hours after intravascular hemolysis induction. We collected serum, urine and tissues sample. We analyzed renal function, oxidative stress, cell death and inflammation in these samples. In other experiments, wild type mice were treated with GKT137831 (10mg/kg/day), a potent Nox4 and Nox1 inhibitor, and mice were sacrificed 72h after induction of hemolysis. We also performed in vitro experiments in murine tubular epithelial cells (MCT) and murine podocytes cells to investigate the regulation of Nox4 in Hb-stimulated cells treated or not with GKT137831. Results Induction of intravascular hemolysis in Nox4+/+ mice increased creatinine and BUN levels and enhanced the expression of tubular injury markers, such as NGAL. These pathological effects were reduced in Nox4 knockout mice. Then, we analyzed oxidative stress in our experimental model thought determination of HO-1, ferritin, GSH and lipid peroxidation levels. All of these oxidative markers were reduced in Nox4-/- mice with intravascular hemolysis as compared with Nox4+/+ mice. We also observed that inflammatory markers such as IL-6, cell death and podocytes injury markers were reduced in Nox4-/- mice than in wild type mice, specially 72 hours after phenylhydrazine injection. In line with these results, GKT137831 administration ameliorated intravascular hemolysis-associated renal function impairment. Moreover, oxidative stress, tubular injury markers and podocyte injury were reduced in hemolytic mice treated with GKT137831. GKT137831 also reduced Hb- and heme-mediated oxidative stress in MCT and podocytes. Conclusion Our results show the important role of Nox4 in renal injury associated to massive intravascular hemolysis. Moreover, the inhibition of Nox4 may be a potential therapeutic target to prevent renal damage associated to Hb accumulation. These findings provide new insights into novel aspects of Hb-toxicity and may have important pathogenic and therapeutic implications for intravascular hemolysis related diseases

scholarly journals The Kidney Injury Induced by Short-Term PM2.5 Exposure and the Prophylactic Treatment of Essential Oils in BALB/c Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Yining Zhang ◽  
Qiujuan Li ◽  
Mengxiong Fang ◽  
Yanmin Ma ◽  
Na Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Inflammatory Response ◽  
Essential Oils ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Kidney Damage ◽  
Ros Generation ◽  
Short Term ◽  
Ras Activation

PM2.5 is well known as a major environmental pollutant; it has been proved to be associated with kidney diseases. The kidney damage involves oxidative stress and/or inflammatory response. NOX4 is a major source of reactive oxygen species (ROS) generation in the kidney, and the excessive generation of ROS is recognized to be responsible for oxidative stress. To elucidate whether short-term PM2.5 exposure could induce kidney damage, we exposed BALB/c mice to PM2.5 intratracheally and measured the biomarkers of kidney injury (KIM-1, cystatin C), oxidative stress (MDA, SOD-1, and HO-1), and inflammatory response (NF-κB, TNF-α). Acute kidney damage and excessive oxidative stress as well as transient inflammatory response were observed after PM2.5 installation. The overexpression of some components of the angiotensin system (RAS) after PM2.5 exposure illustrated that RAS may be involved in PM2.5-induced acute kidney injury. CEOs (compound essential oils) have been widely used because of their antioxidant and anti-inflammation properties. Treatment with CEOs substantially attenuated PM2.5-induced acute kidney injury. The suppression of RAS activation was significant and earlier than the decrease of oxidative stress and inflammatory response after CEOs treatment. We hypothesized that CEOs could attenuate the acute kidney injury by suppressing the RAS activation and subsequently inhibit the oxidative stress and inflammatory response.

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