Ischemia-reperfusion induces renal tubule pyroptosis via the CHOP-caspase-11 pathway

2014 ◽  
Vol 306 (1) ◽  
pp. F75-F84 ◽  
Author(s):  
Ju-Rong Yang ◽  
Feng-Hua Yao ◽  
Jian-Guo Zhang ◽  
Zhi-Yong Ji ◽  
Kai-Long Li ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Er Stress ◽  
Renal Tubule ◽  
Ischemia Reperfusion Injury ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Tissue ◽  
Renal Ischemia ◽  
Cell Death Pathway

The apoptotic or necrotic death of renal tubule epithelial cells is the main pathogenesis of renal ischemia-reperfusion-induced acute kidney injury (AKI). Pyroptosis is a programmed cell death pathway that depends on the activation of the caspase cascade and IL-1 cytokine family members. However, the role of pyroptosis in AKI induced by ischemia-reperfusion remains unclear. In this study, we found that the levels of the pyroptosis-related proteins, including caspase-1, caspase-11, and IL-1β, were significantly increased after 6 h of renal ischemia-reperfusion injury (IRI) and peaked at 12 h after IRI. Enhanced pyroptosis was accompanied by elevated renal structural and functional injury. Similarly, hypoxia-reoxygenation injury (HRI) also induced pyroptosis in renal tubule epithelial NRK-52E cells, which was characterized by increased pore formation and elevated lactate dehydrogenase release. In addition, obvious upregulation of the endoplasmic reticulum (ER) stress biomarkers glucose-regulated protein 78 and C/EBP homologous protein (CHOP) preceded the incidence of pyroptosis in cells treated with IRI or HRI. Pretreatment with a low dose of tunicamycin, an inducer of ER stress, relieved IRI-induced pyroptosis and renal tissue injury. Silencing of CHOP by small interfering RNA significantly decreased HRI-induced pyroptosis of NRK-52E cells, as evidenced by reduced caspase-11 activity and IL-1β generation. Therefore, we conclude that pyroptosis of renal tubule epithelial cells is a key event during IRI and that CHOP-caspase-11 triggered by overactivated ER stress may be an essential pathway involved in pyroptosis.

scholarly journals Targeting HIF-1α to Prevent Renal Ischemia-Reperfusion Injury: Does It Work?

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Kapil Sethi ◽  
Kenny Rao ◽  
Damien Bolton ◽  
Oneel Patel ◽  
Joseph Ischia
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Arterial Occlusion ◽  
Small Animal ◽  
Kidney Injury ◽  
Renal Ischemia ◽  
Metabolic Adaptation ◽  
Critical Ischemia

Partial nephrectomy (open or minimally invasive) usually requires temporary renal arterial occlusion to limit intraoperative bleeding and improve access to intrarenal structures. This is a time-critical step due to the critical ischemia period of renal tissue. Prolonged renal ischemia may lead to irreversible nephron damage in the remaining tissue and, ultimately, chronic kidney disease. This is potentiated by the incompletely understood ischemia-reperfusion injury (IRI). A key mechanism in IRI prevention appears to be the upregulation of an intracellular transcription protein, Hypoxia-Inducible Factor (HIF). HIF mediates metabolic adaptation, angiogenesis, erythropoiesis, cell growth, survival, and apoptosis. Upregulating HIF-1α via ischemic preconditioning (IPC) or drugs that simulate hypoxia (hypoxia-mimetics) has been investigated as a method to reduce IRI. While many promising chemical agents have been trialed for the prevention of IRI in small animal studies, all have failed in human trials. The aim of this review is to highlight the techniques and drugs that target HIF-1α and ameliorate IRI associated with renal ischemia. Developing a technique or drug that could reduce the risk of acute kidney injury associated with renal IRI would have an immediate worldwide impact on multisystem surgeries that would otherwise risk ischemic tissue injury.

scholarly journals Scintigraphic, histopathologic and biochemical evaluation of lycopene effects on renal ischemia reperfusion injury in rats

2017 ◽  
Vol 145 (3-4) ◽  
pp. 153-158 ◽  
Author(s):  
Murat Sadic ◽  
Hasan Atilgan ◽  
Arif Aydin ◽  
Gökhan Koca ◽  
Meliha Korkmaz ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Sham Group ◽  
Ischemia Reperfusion Injury ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Renal Tissue ◽  
Renal Ischemia ◽  
Control Group ◽  
Albino Rats ◽  
Renal Ischemia Reperfusion Injury

Introduction/Objective. Medical protection of kidneys against ischemia reperfusion injury is very important. Many agents have been used for the protection of ischemia reperfusion renal tissue injury. We aimed to evaluate the radioprotective effect of lycopene on kidneys in ischemia reperfusion injury with histopathological, biochemical, and scintigraphic parameters. Methods. Twenty-one Wistar male albino rats were divided into the following three groups: lycopene, control, and sham group. In the lycopene group, lycopene was started three days before right renal ischemia reperfusion injury and continued for 15 days. In the control group, right renal ischemia reperfusion injury was applied with no medication. In the sham group, neither right renal ischemia reperfusion injury nor medication were applied. On the 15th day, all rats were sacrificed after 99mTc-dimercaptosuccinic acid (DMSA) scintigraphies were taken. Histopathological, biochemical, and scintigraphic evaluations were made. Results. The histopathological score was lower in the lycopene group. In biochemical analysis, myeloperoxidase levels were lower in the lycopene group than in the control group, but not statistically significant. Malondialdehyde and nitrite levels were lower in the lycopene group than in the control group. The postoperative mean 99mTc-DMSA uptake values were 44.82 ? 1.84 in the lycopene group, 38.92 ? 1.17 in the control group, and 50.21 ? 1.35 in the sham group. DMSA uptake values were higher in the lycopene group than in the control group. Conclusion. Lycopene seems to be an effective agent for protection of kidneys in ischemia reperfusion injury as demonstrated by the histopathological, biochemical, and scintigraphic parameters.

scholarly journals P0539NICOTIFLORIN ATTENUATES RENAL ISCHEMIA/REPERFUSION INJURY THROUGH REDUCING CELL APOPTOSIS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Lin Wang ◽  
Yan Xu
Keyword(s):  
Acute Kidney Injury ◽  
Epithelial Cells ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Ischemia ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Renal Tubular

Abstract Background and Aims Renal ischemia/reperfusion (I/R) is the main cause for acute kidney injury, Nicotiflorin can ameliorate ischemia/reperfusion injury in other organs, just like in cerebral ischemic damage. Therefore, this article intends to explore whether Nicotiflorin has protective effects on renal tubular epithelial cell after ischemia-reperfusion. On the one hand, We use C57 mice to establish the Nicotiflorin group, DMSO group, AKI group, sham group and control group to investigate whether Nicotiflorin can ameliorate ischemia-reperfusion injury of kidney. In other hand, we use CCK8 to explore the optimal concentration of Nicotiflorin in renal tubular epithelial cells and find optimal hypoxia oxygenation time, in order to analysis the influence of Nicotiflorin. The results indicate that Nicotiflorin can alleviate ischemia-reperfusion injury by reducing apoptosis of renal tubular epithelial cells. Method In this study, we investigated the protective mechanism of Nicotiflorin on ischemic acute kidney injury by analyzing gene chip in patients with acute kidney injury and proving in vitro and in vivo experiments. The main methods are as follows: (1) Multiple nucleus ischemia-reperfusion model transcriptase data were selected from the NCBI GEO Datasets database and analyzed to screen out related proteins that may be involved in ischemia-reperfusion kidney injury; (2) The tertiary structure of Nicotiflorin and related proteins was obtained from the SWISS-MODEL database and the PubChem compound database. The molecular docking between protein and Nicotiflorin was performed using Autodock software, and the binding energy between Nicotiflorin and the selected protein was analyzed to determine Nicotiflorin binds to each other; (3) We set different groups, such as control group, sham group, AKI group, Nicotiflorin group and DMSO group in animals. The blood function was used to detect renal injury related function indicators 24 hours after modeling. Renal tissue samples were collected for real-time fluorescent RT-PCR, Western blotting and histopathological analysis; (4)Renal tubular epithelial cells were treated with different concentrations of Nicotiflorin, CCK8 was screened for the most appropriate concentration, and the hypoxic and reoxygenated cells were intervened at the concentration to explore the interaction between Nicotiflorin and the docking protein, and to observe the protective mechanism of Nicotiflorin on the kidney Results Conclusion Nicotiflorin binds to ATF3 and promotes the expression of Cyr61 through protein interactions to improve renal ischemia-reperfusion injury.

scholarly journals Diet Significantly Influences the Immunopathology and Severity of Kidney Injury in Male C57Bl/6J Mice in a Model Dependent Manner

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1521
Author(s):  
John E. Brus ◽  
Daniel L. Quan ◽  
Kristin J. Wiley ◽  
Brittney Browning ◽  
Hannah Ter Haar ◽  
...  
Keyword(s):  
Animal Studies ◽  
Ischemia Reperfusion Injury ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Tissue ◽  
Chow Diet ◽  
Dependent Manner ◽  
Renal Hypertrophy ◽  
Expression Of Genes

Diet is a leading causative risk factor for morbidity and mortality worldwide, yet it is rarely considered in the design of preclinical animal studies. Several of the nutritional inadequacies reported in Americans have been shown to be detrimental to kidney health; however, the mechanisms responsible are unclear and have been largely attributed to the development of diabetes or hypertension. Here, we set out to determine whether diet influences the susceptibility to kidney injury in male C57Bl/6 mice. Mice were fed a standard chow diet, a commercially available “Western” diet (WD), or a novel Americanized diet (AD) for 12 weeks prior to the induction of kidney injury using the folic acid nephropathy (FAN) or unilateral renal ischemia reperfusion injury (uIRI) models. In FAN, the mice that were fed the WD and AD had worse histological evidence of tissue injury and greater renal expression of genes associated with nephrotoxicity and monocyte infiltration as compared to mice fed chow. Mice fed the AD developed more severe renal hypertrophy following FAN, and gene expression data suggest the mechanism for FAN differed among the diets. Meanwhile, mice fed the WD had the greatest circulating interleukin-6 concentrations. In uIRI, no difference was observed in renal tissue injury between the diets; however, mice fed the WD and AD displayed evidence of suppressed inflammatory response. Taken together, our data support the hypothesis that diet directly impacts the severity and pathophysiology of kidney disease and is a critical experimental variable that needs to be considered in mechanistic preclinical animal studies.

scholarly journals Ascorbic acid improves renal microcirculatory oxygenation in a rat model of renal I/R injury

2015 ◽  
Vol 3 (3) ◽  
pp. 116-125 ◽  
Author(s):  
Bulent Ergin ◽  
Coert J. Zuurbier ◽  
Rick Bezemer ◽  
Asli Kandil ◽  
Emre Almac ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Ascorbic Acid ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Tissue ◽  
Control Group ◽  
Free Oxygen Radicals ◽  
Time Control ◽  
Inflammatory Parameters

AbstractBackground and objectives: Acute kidney injury (AKI) is a clinical condition associated with a degree of morbidity and mortality despite supportive care, and ischemia/reperfusion injury (I/R) is one of the main causes of AKI. The pathophysiology of I/R injury is a complex cascade of events including the release of free oxygen radicals followed by damage to proteins, lipids, mitochondria, and deranged tissue oxygenation. In this study, we investigated whether the antioxidant ascorbic acid would be able to largely prevent oxidative stress and consequently, reduce I/R-related injury to the kidneys in terms of oxygenation, inflammation, and renal failure. Materials and methods: Rats were divided into three groups (n = 6/group): (1) a time control group; (2) a group subjected to renal ischemia for 60 min by high aortic occlusion followed by 2 h of reperfusion (I/R); and (3) a group subjected to I/R and treated with an i.v. 100 mg/kg bolus ascorbic acid 15 min before ischemia and continuous infusion of 50 mg/kg/hour for 2 h during reperfusion (I/R + AA). We measured renal tissue oxidative stress, microvascular oxygenation, renal oxygen delivery and consumption, and renal expression of inflammatory and injury markers. Results: We demonstrated that aortic clamping and release resulted in increased oxidative stress and inflammation that was associated with a significant fall in systemic and renal hemodynamics and oxygenation parameters. The treatment of ascorbic acid completely abrogated oxidative stress and inflammatory parameters. However, it only partly improved microcirculatory oxygenation and was without any effect on anuria. Conclusion: The ascorbic acid treatment partly improves microcirculatory oxygenation and prevents oxidative stress without restoring urine output in a severe I/R model of AKI.

scholarly journals Arginase-2 mediates renal ischemia-reperfusion injury

2017 ◽  
Vol 313 (2) ◽  
pp. F522-F534 ◽  
Author(s):  
Wesley M. Raup-Konsavage ◽  
Ting Gao ◽  
Timothy K. Cooper ◽  
Sidney M. Morris ◽  
W. Brian Reeves ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Blood Urea Nitrogen ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Ischemia ◽  
Arginase Activity ◽  
Urea Nitrogen ◽  
The Impact ◽  
Novel Therapeutic

Novel therapeutic interventions for preventing or attenuating kidney injury following ischemia-reperfusion injury (IRI) remain a focus of significant interest. Currently, there are no definitive therapeutic or preventive approaches available for ischemic acute kidney injury (AKI). Our objective is to determine 1) whether renal arginase activity or expression is increased in renal IRI, and 2) whether arginase plays a role in development of renal IRI. The impact of arginase activity and expression on renal damage was evaluated in male C57BL/6J (wild type) and arginase-2 (ARG2)-deficient ( Arg2−/−) mice subjected to bilateral renal ischemia for 28 min, followed by reperfusion for 24 h. ARG2 expression and arginase activity significantly increased following renal IRI, paralleling the increase in kidney injury. Pharmacological blockade or genetic deficiency of Arg2 conferred kidney protection in renal IRI. Arg2−/− mice had significantly attenuated kidney injury and lower plasma creatinine and blood urea nitrogen levels after renal IRI. Blocking arginases using S-(2-boronoethyl)-l-cysteine (BEC) 18 h before ischemia mimicked arginase deficiency by reducing kidney injury, histopathological changes and kidney injury marker-1 expression, renal apoptosis, kidney inflammatory cell recruitment and inflammatory cytokines, and kidney oxidative stress; increasing kidney nitric oxide (NO) production and endothelial NO synthase (eNOS) phosphorylation, kidney peroxisome proliferator-activated receptor-γ coactivator-1α expression, and mitochondrial ATP; and preserving kidney mitochondrial ultrastructure compared with vehicle-treated IRI mice. Importantly, BEC-treated eNOS-knockout mice failed to reduce blood urea nitrogen and creatinine following renal IRI. These findings indicate that ARG2 plays a major role in renal IRI, via an eNOS-dependent mechanism, and that blocking ARG2 activity or expression could be a novel therapeutic approach for prevention of AKI.

scholarly journals Histone acetylation and DNA methylation in ischemia/reperfusion injury

2019 ◽  
Vol 133 (4) ◽  
pp. 597-609 ◽  
Author(s):  
Jinhua Tang ◽  
Shougang Zhuang
Keyword(s):  
Dna Methylation ◽  
Ischemia Reperfusion Injury ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Circulatory Arrest ◽  
Kidney Injury ◽  
High Morbidity ◽  
Epigenetic Alterations ◽  
Injury Causes ◽  
Potential Therapeutics

Abstract Ischemic/reperfusion (I/R) injury causes a series of serious clinical problems associated with high morbidity and mortality in various disorders, such as acute kidney injury (AKI), myocardial infarction, ischemic stroke, circulatory arrest, and peripheral vascular disease. The pathophysiology and pathogenesis of I/R injury is complex and multifactorial. Recent studies have revealed that epigenetic regulation is critically involved in the pathogenesis of I/R-induced tissue injury. In this review, we will sum up recent advances on the modification, regulation, and implication of histone modifications and DNA methylation in I/R injury-induced organ dysfunction. Understandings of I/R-induced epigenetic alterations and regulations will aid in the development of potential therapeutics.

scholarly journals Cell Death Patterns Due to Warm Ischemia or Reperfusion in Renal Tubular Epithelial Cells Originating from Human, Mouse, or the Native Hibernator Hamster

Biology ◽  
2018 ◽  
Vol 7 (4) ◽  
pp. 48 ◽  
Author(s):  
Theodoros Eleftheriadis ◽  
Georgios Pissas ◽  
Georgia Antoniadi ◽  
Vassilios Liakopoulos ◽  
Ioannis Stefanidis
Keyword(s):  
Lipid Peroxidation ◽  
Acute Kidney Injury ◽  
Cell Death ◽  
Epithelial Cells ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Human Cells ◽  
Tubular Epithelial Cells

Ischemia–reperfusion injury contributes to the pathogenesis of many diseases, with acute kidney injury included. Hibernating mammals survive prolonged bouts of deep torpor with a dramatic drop in blood pressure, heart, and breathing rates, interspersed with short periods of arousal and, consequently, ischemia–reperfusion injury. Clarifying the differences under warm anoxia or reoxygenation between human cells and cells from a native hibernator may reveal interventions for rendering human cells resistant to ischemia–reperfusion injury. Human and hamster renal proximal tubular epithelial cells (RPTECs) were cultured under warm anoxia or reoxygenation. Mouse RPTECs were used as a phylogenetic control for hamster cells. Cell death was assessed by both cell imaging and lactate dehydrogenase (LDH) release assay, apoptosis by cleaved caspase-3, autophagy by microtubule-associated protein 1-light chain 3 B II (LC3B-II) to LC3B-I ratio, necroptosis by phosphorylated mixed-lineage kinase domain-like pseudokinase, reactive oxygen species (ROS) fluorometrically, and lipid peroxidation, the end-point of ferroptosis, by malondialdehyde. Human cells died after short periods of warm anoxia or reoxygenation, whereas hamster cells were extremely resistant. In human cells, apoptosis contributed to cell death under both anoxia and reoxygenation. Although under reoxygenation, ROS increased in both human and hamster RPTECs, lipid peroxidation-induced cell death was detected only in human cells. Autophagy was observed only in human cells under both conditions. Necroptosis was not detected in any of the evaluated cells. Clarifying the ways that are responsible for hamster RPTECs escaping from apoptosis and lipid peroxidation-induced cell death may reveal interventions for preventing ischemia–reperfusion-induced acute kidney injury in humans.

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