scholarly journals Inhibition of HDAC3 protects against kidney cold storage/transplantation injury and allograft dysfunction

2021 ◽  
Author(s):  
Xiaohong Xiang ◽  
Guie Dong ◽  
Jiefu Zhu ◽  
Gang Zhang ◽  
Zheng Dong
Keyword(s):  
Cell Death ◽  
Kidney Transplantation ◽  
Cold Storage ◽  
Ischemia Reperfusion Injury ◽  
Therapeutic Option ◽  
Ischemia Reperfusion ◽  
Dynamic Change ◽  
Graft Function ◽  
Recipient Mouse

Cold storage/rewarming is an inevitable process for kidney transplantation from deceased donors, which correlates closely with renal ischemia-reperfusion injury (IRI) and the occurrence of delayed graft function. Histone deacetylases (HDAC) are important epigenetic regulators but their involvement in cold storage/rewarming injury in kidney transplantation is unclear. In the present study, we showed a dynamic change of HDAC3 in a mouse model of kidney cold storage followed by transplantation. We then demonstrated that the selective HDAC3 inhibitor RGFP966 could reduce acute tubular injury and cell death after prolonged cold storage with transplantation. RGFP966 also improved renal function, kidney repair and tubular integrity when the transplanted kidney became the sole life-supporting graft in the recipient mouse. In vitro, cold storage of proximal tubular cells followed by rewarming induced remarkable cell death, which was suppressed by RGFP966 or knockdown of HDAC3 with shRNA. Inhibition of HDAC3 decreased the mitochondrial pathway of apoptosis and preserved mitochondrial membrane potential. Collectively, HDAC3 plays a pathogenic role in cold storage/rewarming injury in kidney transplantation and its inhibition may be a therapeutic option.

scholarly journals Molecular Aspects of Volatile Anesthetic-Induced Organ Protection and Its Potential in Kidney Transplantation

2021 ◽  
Vol 22 (5) ◽  
pp. 2727
Author(s):  
Gertrude J. Nieuwenhuijs-Moeke ◽  
Dirk J. Bosch ◽  
Henri G.D. Leuvenink
Keyword(s):  
Kidney Transplantation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Animal Experiments ◽  
Volatile Anesthetic ◽  
Organ Protection ◽  
Graft Outcome ◽  
Molecular Aspects

Ischemia reperfusion injury (IRI) is inevitable in kidney transplantation and negatively impacts graft and patient outcome. Reperfusion takes place in the recipient and most of the injury following ischemia and reperfusion occurs during this reperfusion phase; therefore, the intra-operative period seems an attractive window of opportunity to modulate IRI and improve short- and potentially long-term graft outcome. Commonly used volatile anesthetics such as sevoflurane and isoflurane have been shown to interfere with many of the pathophysiological processes involved in the injurious cascade of IRI. Therefore, volatile anesthetic (VA) agents might be the preferred anesthetics used during the transplantation procedure. This review highlights the molecular and cellular protective points of engagement of VA shown in in vitro studies and in vivo animal experiments, and the potential translation of these results to the clinical setting of kidney transplantation.

Abstract 205: Recovery from Ischemia-Reperfusion Injury Is Metabolic Substrate-Dependent

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Sergiy M Nadtochiy ◽  
Paul S Brookes
Keyword(s):  
Cell Death ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Lactate Production ◽  
Protective Role ◽  
Reserve Capacity ◽  
Similar Response ◽  
Fat Cells ◽  
Metabolic Reserve

Introduction: The adult heart utilizes mostly fat for energy production, with adaptation to different fuels (“metabolic plasticity”) being a hallmark of the healthy heart. However, metabolic maladaptation is known to occur in heart failure. As such, the ability of the heart to metabolize specific substrates could impact the outcome of pathological insults, such as ischemia-reperfusion (IR) injury. The aim of this study was to develop a system whereby adult mouse cardiomyocytes (AMC) subjected to IR injury could be supplied with different fuels, and metabolism measured in real-time. Methods: AMC were divided in 3 groups, supplied either with glucose (GLU, 5mM), palmitate/fat free BSA (FAT, 100µM) or GLU+FAT. A previously developed method for in-vitro IR injury using a Seahorse XF24 [1], was adopted for ACM. IR comprised 60 min. ischemia and 60 min. reperfusion, and additional metabolic parameters were measured separately using mitochondrial inhibitors and uncouplers [2]. Oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were simultaneously measured during the IR protocol, followed by a cell death assay. Results: FAT cells showed higher baseline OCR and lower ECAR rates compare to GLU cells, although uncoupled OCR was lower in FAT group, suggesting a lower metabolic reserve capacity for cells respiring on fat. Upon IR, the drop in pH was significantly greater in GLU compare to FAT, indicating faster lactate production. During reperfusion, both OCR and ECAR recovered to pre-ischemic levels in GLU cells but failed to do so in FAT cells. Post-IR cell death was significantly higher in FAT vs. GLU. Surprisingly, GLU+FAT (modeling a “physiologic” substrate mix) replicated the same metabolic profile and cell death as GLU. Conclusions: (i) AMC had better recovery from IR injury using glucose as fuel. (ii) Lower cell viability in FAT (vs. GLU) correlated with smaller metabolic reserve capacity and with a smaller pH drop during ischemia. This is consistent with a known protective role for acidification during IR injury. (iii) Mixed substrates (GLU+FAT) gave a similar response to glucose alone, suggesting that fat may not be toxic, rather glucose is protective, in IR injury. [1] Circ Res. (2012), 110. 948-57. [2] J Vis Exp. (2010), 46. pii: 2511.

scholarly journals Up-regulation of MicroRNA-21 Mediates Isoflurane-induced Protection of Cardiomyocytes

2015 ◽  
Vol 122 (4) ◽  
pp. 795-805 ◽  
Author(s):  
Jessica M. Olson ◽  
Yasheng Yan ◽  
Xiaowen Bai ◽  
Zhi-Dong Ge ◽  
Mingyu Liang ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Messenger Rna ◽  
Functional Role ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cell Death Protein

Abstract Background: Anesthetic cardioprotection reduces myocardial infarct size after ischemia–reperfusion injury. Currently, the role of microRNA in this process remains unknown. MicroRNAs are short, noncoding nucleotide sequences that negatively regulate gene expression through degradation or suppression of messenger RNA. In this study, the authors uncovered the functional role of microRNA-21 (miR-21) up-regulation after anesthetic exposure. Methods: MicroRNA and messenger RNA expression changes were analyzed by quantitative real-time polymerase chain reaction in cardiomyocytes after exposure to isoflurane. Lactate dehydrogenase release assay and propidium iodide staining were conducted after inhibition of miR-21. miR-21 target expression was analyzed by Western blot. The functional role of miR-21 was confirmed in vivo in both wild-type and miR-21 knockout mice. Results: Isoflurane induces an acute up-regulation of miR-21 in both in vivo and in vitro rat models (n = 6, 247.8 ± 27.5% and 258.5 ± 9.0%), which mediates protection to cardiomyocytes through down-regulation of programmed cell death protein 4 messenger RNA (n = 3, 82.0 ± 4.9% of control group). This protective effect was confirmed by knockdown of miR-21 and programmed cell death protein 4 in vitro. In addition, the protective effect of isoflurane was abolished in miR-21 knockout mice in vivo, with no significant decrease in infarct size compared with nonexposed controls (n = 8, 62.3 ± 4.6% and 56.2 ± 3.2%). Conclusions: The authors demonstrate for the first time that isoflurane mediates protection of cardiomyocytes against oxidative stress via an miR-21/programmed cell death protein 4 pathway. These results reveal a novel mechanism by which the damage done by ischemia/reperfusion injury may be decreased.

scholarly journals Corin Is Downregulated in Renal Ischemia/Reperfusion Injury and Is Associated with Delayed Graft Function after Kidney Transplantation

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Xinyi Hu ◽  
Ming Su ◽  
Jun Lin ◽  
Lei Zhang ◽  
Wen Sun ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Differentially Expressed Genes ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Graft Function ◽  
Renal Ischemia ◽  
Delayed Graft Function ◽  
Differentially Expressed ◽  
Potential Biomarker ◽  
Renal Ischemia Reperfusion Injury

Renal ischemia/reperfusion (IR) injury is one of the most important risk factors for the occurrence of delayed graft function (DGF) after kidney transplantation; however, its mechanism remains not fully understood. In the present study, we screened differentially expressed genes in a murine model of renal IR injury by using high-throughput assays. We identified Corin as one of the most significantly downregulated genes among 2218 differentially expressed genes (≥2-fold, P<0.05). By using a real-time qPCR assay, we observed that the expression of renal Corin in IR-injured mice was reduced to 11.5% of the sham-operated mice and that the protein level of renal Corin in IR-injured mice was also downregulated. Interestingly, renal IR injury in mice induced the downregulation of Corin in heart tissues, suggesting that the overall synthesis of Corin may be suppressed. We recruited 11 recipients complicated with DGF and 16 without DGF, and plasma Corin concentrations were determined by ELISA. We observed that the plasma Corin levels were indeed reduced in recipients complicated with DGF (0.98 vs. 1.95 ng/ml, P<0.05). These findings demonstrate that Corin may be a potential biomarker of DGF after kidney transplantation and may participate in the regulation of renal IR injury.

Roles of TRPM7 in Renal Ischemia-Reperfusion Injury

2019 ◽  
Vol 20 (8) ◽  
pp. 777-788 ◽  
Author(s):  
Aifen Liu ◽  
Bin Yang
Keyword(s):  
Reperfusion Injury ◽  
Transient Receptor Potential ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Dynamic Change ◽  
Health Concern ◽  
High Morbidity ◽  
Transient Receptor Potential Melastatin ◽  
Potential Biomarker

: Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI) that is a global health concern associated with high morbidity and mortality. So far, no specific interventions limit injury or improve recovery and survival. Transient receptor potential melastatin 7 (TRPM7), a bifunctional membrane protein, plays key roles in inflammation and cell death. However, the precise role and under-lying mechanism of TRPM7 in IR-induced AKI have not been well defined. Herein, we reviewed the structure and function of TRPM7 as a non-selective ion channel, but Ca2+ and Mg2+-conducting, that mediated the elevation of cytosolic Ca2+ and Mg2+. We then reviewed the mechanism of TRPM7 involved in the pathophysiology of IRI, including inflammatory response, apoptosis and necroptosis, renal microvasculature, as well as maladaptive fibrogenesis leading to chronic kidney disease (CKD). Our previous study has shown that the dynamic change and underlying mechanism of TRPM7 involving in inflammation and apoptosis in in vitro hypoxia/reoxygenation and in vivo renal IRI models. The association between TRPM7, apoptosis and inflammation, as well as related caspase-3, HMGB1 and Bax/Bcl-2 ratio, was also discussed. Disclosing the involvement of TRPM7 in renal IRI might provide new mechanistic insights for a potential biomarker as diagnostic and therapeutic target of AKI.

scholarly journals Inhibition of Neuronal Necroptosis Mediated by RIPK1 Provides Neuroprotective Effects on Hypoxia and Ischemia In Vitro and In Vivo

2022 ◽  
Vol 23 (2) ◽  
pp. 735
Author(s):  
Elena V. Mitroshina ◽  
Maria M. Loginova ◽  
Roman S. Yarkov ◽  
Mark D. Urazov ◽  
Maria O. Novozhilova ◽  
...  
Keyword(s):  
Cell Death ◽  
Ischemia Reperfusion Injury ◽  
Pathological Condition ◽  
Ischemia Reperfusion ◽  
Laboratory Animals ◽  
Bioelectrical Activity ◽  
Electrode Arrays ◽  
Ischemic Brain

Ischemic brain injury is a widespread pathological condition, the main components of which are a deficiency of oxygen and energy substrates. In recent years, a number of new forms of cell death, including necroptosis, have been described. In necroptosis, a cascade of interactions between the kinases RIPK1 and RIPK3 and the MLKL protein leads to the formation of a specialized death complex called the necrosome, which triggers MLKL-mediated destruction of the cell membrane and necroptotic cell death. Necroptosis probably plays an important role in the development of ischemia/reperfusion injury and can be considered as a potential target for finding methods to correct the disruption of neural networks in ischemic damage. In the present study, we demonstrated that blockade of RIPK1 kinase by Necrostatin-1 preserved the viability of cells in primary hippocampal cultures in an in vitro model of glucose deprivation. The effect of RIPK1 blockade on the bioelectrical and metabolic calcium activity of neuron-glial networks in vitro using calcium imaging and multi-electrode arrays was assessed for the first time. RIPK1 blockade was shown to partially preserve both calcium and bioelectric activity of neuron-glial networks under ischemic factors. However, it should be noted that RIPK1 blockade does not preserve the network parameters of the collective calcium dynamics of neuron-glial networks, despite the maintenance of network bioelectrical activity (the number of bursts and the number of spikes in the bursts). To confirm the data obtained in vitro, we studied the effect of RIPK1 blockade on the resistance of small laboratory animals to in vivo modeling of hypoxia and cerebral ischemia. The use of Necrostatin-1 increases the survival rate of C57BL mice in modeling both acute hypobaric hypoxia and ischemic brain damage.

scholarly journals Overexpression and pre-treatment of recombinant human Secretory Leukocyte Protease Inhibitor (rhSLPI) reduces an in vitro ischemia/reperfusion injury in rat cardiac myoblast (H9c2) cell

2018 ◽  
Vol 9 (1) ◽  
pp. 17-32 ◽  
Author(s):  
Eakkapote Prompunt ◽  
Nitirut Nernpermpisooth ◽  
Jantira Sanit ◽  
Sarawut Kumphune
Keyword(s):  
Cell Death ◽  
Protease Inhibitor ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Secretory Leukocyte Protease Inhibitor ◽  
H9c2 Cell ◽  
Cardiac Cell ◽  
H9c2 Cells ◽  
Akt Phosphorylation

AbstractOne of the major causes of cardiac cell death during myocardial ischemia is the oversecretion of protease enzymes surrounding the ischemic tissue. Therefore, inhibition of the protease activity could be an alternative strategy for preventing the expansion of the injured area. In the present study, we investigated the effects of Secretory Leukocyte Protease Inhibitor (SLPI), by means of overexpression and treatment of recombinant human SLPI (rhSLPI) in an in vitro model. Rat cardiac myoblast (H9c2) cells overexpressing rhSLPI were generated by gene delivery using pCMV2-SLPI-HA plasmid. The rhSLPI-H9c2 cells, mock transfected cells, and wild-type (WT) control were subjected to simulated ischemia/reperfusion (sI/R). Moreover, the treatment of rhSLPI in H9c2 cells was also performed under sI/R conditions. The results showed that overexpression of rhSLPI in H9c2 cells significantly reduced sI/R-induced cell death and injury, intracellular ROS level, and increased Akt phosphorylation, when compared to WT and mock transfection (p <0.05). Treatment of rhSLPI prior to sI/R reduced cardiac cell death and injury, and intra-cellular ROS level. In addition, 400 ng/ml rhSLPI treatment, prior to sI, significantly inhibited p38 MAPK phosphorylation and rhSLPI at 400–1000 ng/ml could increase Akt phosphorylation.

scholarly journals Critical Roles of Calpastatin in Ischemia/Reperfusion Injury in Aged Livers

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1863
Author(s):  
Joseph Flores-Toro ◽  
Sung-Kook Chun ◽  
Jun-Kyu Shin ◽  
Joan Campbell ◽  
Melissa Lichtenberger ◽  
...  
Keyword(s):  
Cell Death ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Age Groups ◽  
Permeability Transition ◽  
Mitochondrial Morphology ◽  
Human And Mouse

Ischemia/reperfusion (I/R) injury unavoidably occurs during hepatic resection and transplantation. Aged livers poorly tolerate I/R during surgical treatment. Although livers have a powerful endogenous inhibitor of calpains, calpastatin (CAST), I/R activates calpains, leading to impaired autophagy, mitochondrial dysfunction, and hepatocyte death. It is unknown how I/R in aged livers affects CAST. Human and mouse liver biopsies at different ages were collected during in vivo I/R. Hepatocytes were isolated from 3-month- (young) and 26-month-old (aged) mice, and challenged with short in vitro simulated I/R. Cell death, protein expression, autophagy, and mitochondrial permeability transition (MPT) between the two age groups were compared. Adenoviral vector was used to overexpress CAST. Significant cell death was observed only in reperfused aged hepatocytes. Before the commencement of ischemia, CAST expression in aged human and mouse livers and mouse hepatocytes was markedly greater than that in young counterparts. However, reperfusion substantially decreased CAST in aged human and mouse livers. In hepatocytes, reperfusion rapidly depleted aged cells of CAST, cleaved autophagy-related protein 5 (ATG5), and induced defective autophagy and MPT onset, all of which were blocked by CAST overexpression. Furthermore, mitochondrial morphology was shifted toward an elongated shape with CAST overexpression. In conclusion, CAST in aged livers is intrinsically short-lived and lost after short I/R. CAST depletion contributes to age-dependent liver injury after I/R.

scholarly journals Adipose-Derived Stem/Stromal Cells in Kidney Transplantation: Status Quo and Future Perspectives

2021 ◽  
Vol 22 (20) ◽  
pp. 11188
Author(s):  
Gabriele Storti ◽  
Evaldo Favi ◽  
Francesca Albanesi ◽  
Bong-Sung Kim ◽  
Valerio Cervelli
Keyword(s):  
Kidney Transplantation ◽  
Stromal Cells ◽  
Ischemia Reperfusion Injury ◽  
Current Knowledge ◽  
Ischemia Reperfusion ◽  
Graft Function ◽  
Future Perspective ◽  
Stage Renal Disease ◽  
End Stage ◽  
The Impact

Kidney transplantation (KT) is the gold standard treatment of end-stage renal disease. Despite progressive advances in organ preservation, surgical technique, intensive care, and immunosuppression, long-term allograft survival has not significantly improved. Among the many peri-operative complications that can jeopardize transplant outcomes, ischemia–reperfusion injury (IRI) deserves special consideration as it is associated with delayed graft function, acute rejection, and premature transplant loss. Over the years, several strategies have been proposed to mitigate the impact of IRI and favor tolerance, with rather disappointing results. There is mounting evidence that adipose stem/stromal cells (ASCs) possess specific characteristics that could help prevent, reduce, or reverse IRI. Immunomodulating and tolerogenic properties have also been suggested, thus leading to the development of ASC-based prophylactic and therapeutic strategies in pre-clinical and clinical models of renal IRI and allograft rejection. ASCs are copious, easy to harvest, and readily expandable in culture. Furthermore, ASCs can secrete extracellular vesicles (EV) which may act as powerful mediators of tissue repair and tolerance. In the present review, we discuss the current knowledge on the mechanisms of action and therapeutic opportunities offered by ASCs and ASC-derived EVs in the KT setting. Most relevant pre-clinical and clinical studies as well as actual limitations and future perspective are highlighted.

scholarly journals Mitochondrial Metabolism behind Region-Specific Resistance to Ischemia-Reperfusion Injury in Gerbil Hippocampus. Role of PKCβII and Phosphate-Activated Glutaminase

2021 ◽  
Vol 22 (16) ◽  
pp. 8504
Author(s):  
Małgorzata Beręsewicz-Haller ◽  
Olga Krupska ◽  
Paweł Bochomulski ◽  
Danuta Dudzik ◽  
Anita Chęcińska ◽  
...  
Keyword(s):  
Cell Death ◽  
Ischemia Reperfusion Injury ◽  
Tricarboxylic Acid Cycle ◽  
Ischemia Reperfusion ◽  
Specific Inhibitor ◽  
Therapeutic Interventions ◽  
Neuronal Viability ◽  
Ischemic Episode ◽  
Phosphate Activated Glutaminase

Ischemic episodes are a leading cause of death worldwide with limited therapeutic interventions. The current study explored mitochondrial phosphate-activated glutaminase (GLS1) activity modulation by PKCβII through GC-MS untargeted metabolomics approach. Mitochondria were used to elucidate the endogenous resistance of hippocampal CA2-4 and dentate gyrus (DG) to transient ischemia and reperfusion in a model of ischemic episode in gerbils. In the present investigation, male gerbils were subjected to bilateral carotids occlusion for 5 min followed by reperfusion (IR). Gerbils were randomly divided into three groups as vehicle-treated sham control, vehicle-treated IR and PKCβII specific inhibitor peptide βIIV5-3-treated IR. Vehicle or βIIV5-3 (3 mg/kg, i.v.) were administered at the moment of reperfusion. The gerbils hippocampal tissue were isolated at various time of reperfusion and cell lysates or mitochondria were isolated from CA1 and CA2-4,DG hippocampal regions. Recombinant proteins PKCβII and GLS1 were used in in vitro phosphorylation reaction and organotypic hippocampal cultures (OHC) transiently exposed to NMDA (25 μM) to evaluate the inhibition of GLS1 on neuronal viability. PKCβII co-precipitates with GAC (GLS1 isoform) in CA2-4,DG mitochondria and phosphorylates GLS1 in vitro. Cell death was dose dependently increased when GLS1 was inhibited by BPTA while inhibition of mitochondrial pyruvate carrier (MPC) attenuated cell death in NMDA-challenged OHC. Fumarate and malate were increased after IR 1h in CA2-4,DG and this was reversed by βIIV5-3 what correlated with GLS1 activity increases and earlier showed elevation of neuronal death (Krupska et al., 2017). The present study illustrates that CA2-4,DG resistance to ischemic episode at least partially rely on glutamine and glutamate utilization in mitochondria as a source of carbon to tricarboxylic acid cycle. This phenomenon depends on modulation of GLS1 activity by PKCβII and remodeling of MPC: all these do not occur in ischemia-vulnerable CA1.

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