scholarly journals Cellular senescence inhibits renal regeneration after injury in mice, with senolytic treatment promoting repair

2021 ◽  
Vol 13 (594) ◽  
pp. eabb0203
Author(s):  
Katie J. Mylonas ◽  
Eoin D. O’Sullivan ◽  
Duncan Humphries ◽  
David P. Baird ◽  
Marie-Helena Docherty ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cellular Senescence ◽  
Transforming Growth Factor ◽  
Ischemia Reperfusion Injury ◽  
Kidney Diseases ◽  
Ischemia Reperfusion ◽  
B Cell Lymphoma ◽  
Senescent Cell ◽  
Causative Role ◽  
Regenerative Capacity

The ability of the kidney to regenerate successfully after injury is lost with advancing age, chronic kidney disease, and after irradiation. The factors responsible for this reduced regenerative capacity remain incompletely understood, with increasing interest in a potential role for cellular senescence in determining outcomes after injury. Here, we demonstrated correlations between senescent cell load and functional loss in human aging and chronic kidney diseases including radiation nephropathy. We dissected the causative role of senescence in the augmented fibrosis occurring after injury in aged and irradiated murine kidneys. In vitro studies on human proximal tubular epithelial cells and in vivo mouse studies demonstrated that senescent renal epithelial cells produced multiple components of the senescence-associated secretory phenotype including transforming growth factor β1, induced fibrosis, and inhibited tubular proliferative capacity after injury. Treatment of aged and irradiated mice with the B cell lymphoma 2/w/xL inhibitor ABT-263 reduced senescent cell numbers and restored a regenerative phenotype in the kidneys with increased tubular proliferation, improved function, and reduced fibrosis after subsequent ischemia-reperfusion injury. Senescent cells are key determinants of renal regenerative capacity in mice and represent emerging treatment targets to protect aging and vulnerable kidneys in man.

scholarly journals Colchicine Attenuates Renal Ischemia-Reperfusion-Induced Liver Damage: Implication of TLR4/NF-κB, TGF-β, BAX and Bcl-2 gene expression

2021 ◽  
Author(s):  
Azza Sayed Awad ◽  
Hemat Abdel Fatah Elariny ◽  
Amany Said Sallam
Keyword(s):  
Gene Expression ◽  
Liver Damage ◽  
Transforming Growth Factor ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
B Cell Lymphoma ◽  
Sham Operation ◽  
Necrosis Factor Alpha ◽  
Sham Operation Group ◽  
Anti Inflammatory

Background: Ischemia/reperfusion injury (IRI) is typically associated with a vigorous inflammatory and oxidative stress response to hypoxia and reperfusion that disturbs the function of the organ. The remote effects of renal IRI on the liver, however, require further study. Renal damage associated with liver disease is a common clinical problem. Colchicine, a polymerization inhibitor of microtubules has been used as an anti-inflammatory and anti-fibrotic drug for liver diseases. Aims: The goal of the current study was to investigate the possible protective mechanisms of colchicine on liver injury following renal IRI. Methods: Forty rats were divided randomly into four groups; group of sham operation, group of colchicine treated, group of IRI, group of colchicine treated-IRI. Key findings: Treatment with colchicine significantly reduced hepatic toll-like receptor 4 {TLR4}, nuclear factor kappa B transcription factor {NF-κB}, myeloid differentiation factor 88 {MyD88}, and tumor necrosis factor-alpha {TNF-α} contents, down-regulated BCL2 Associated X Apoptosis Regulator {BAX} gene expression, transforming growth factor-β {TGF-β} content and upregulated hepatic B-cell lymphoma 2 {Bcl-2} gene expression as compared to the IRI group. Finally, hepatic histopathological examinations have confirmed the biochemical results. Significance: Renal IRI-induced liver damage in rats was alleviated by colchicine through its anti-inflammatory, anti-apoptotic, and anti-fibrotic actions.

Etomidate Alleviates Ischemia-Anoxia Reperfusion Injury in Intestinal Epithelial Cells by Inhibiting the Activation of traf6-Regulated NF-KB Signaling

2022 ◽  
Vol 12 (5) ◽  
pp. 1015-1021
Author(s):  
Gen Lin ◽  
Ruichun Long ◽  
Xiaoqing Yang ◽  
Songsong Mao ◽  
Hongying Li
Keyword(s):  
Oxidative Stress ◽  
Epithelial Cells ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Intestinal Epithelial Cells ◽  
Ischemia Reperfusion ◽  
Stress Factors ◽  
Inflammatory Factors ◽  
Intestinal Cell ◽  
Intestinal Epithelial

Objective: The present study aimed to investigate the role of etomidate in intestinal cell ischemia and hypoxia-reperfusion injury and potential mechanisms. Method: In this study, we establish the intestinal epithelial cells ischemia-reperfusion model in vitro. CCK8 was used to detect cell viability and flow cytometry assay was used to detect apoptosis levels of treated OGD/R model cells. ELISA measured the expression level of oxidative stress factors and inflammatory factors. Furthermore, western blot assay was used to detect the expression the apoptosis-related factors and TNFR-associated factors in treated OGD/R model cells. Result: Etomidate does not affect the activity of intestinal epithelial cells, and can protect intestinal epithelial cells to reduce ischemiareperfusion injury, and the expression of inflammatory factors and oxidative stress in cells with mild intestinal epithelial ischemia-reperfusion injury. Etomidate alleviates apoptosis of intestinal epithelial ischemia-reperfusion injury cells. Etomidate inhibits the activation of traf6-mediated NF-κB signal during ischemia-anoxia reperfusion of intestinal epithelial cells. Conclusion: Taken together, our study demonstrated that etomidate attenuates inflammatory response and apoptosis in intestinal epithelial cells during ischemic hypoxia-reperfusion injury and inhibits activation of NF-κB signaling regulated by TRAF6.

Abstract 782: Fra2 Mediates Oxygen-induced TGFbeta-1 mRNA Expression In Adult Cardiac Fibroblasts: Significance In Myocardial Fibrosis Following Ischemia-reperfusion Injury

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Sashwati Roy ◽  
Savita Khanna ◽  
Chandan K Sen
Keyword(s):  
Mrna Expression ◽  
Transforming Growth Factor Beta ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Ischemia Reperfusion Injury ◽  
Cardiac Fibroblasts ◽  
Ischemia Reperfusion ◽  
Luciferase Reporter ◽  
Mrna Levels

Background . Transforming growth factor beta-1 (TGFbeta-1) is a key cytokine implicated in the development of cardiac fibrosis following ischemia-reperfusion (IR) injury. The profibrotic effects of TGFbeta-1 are primarily attributable to the differentiation of cardiac fibroblasts (CF) to myofibroblasts. Previously, we have reported perceived hyperoxia (Circ Res 92:264 –71), sub-lethal reoxygenation shock during IR, induces differentiation of CF to myofibroblasts at the infarct site. The mechanisms underlying oxygen-sensitive induction of TGFbeta-1 mRNA remain to be characterized. Hypothesis . Fra2 mediates oxygen-induced TGFbeta-1 mRNA expression in adult cardiac fibroblasts. Methods. TGFbeta-1 mRNA expression in infarct tissue was investigated in an IR injury model. The left anterior descending coronary artery of mice was transiently occluded for 60 minutes followed by reperfusion to induce IR injury. Spatially resolved infarct and non-infarct tissues were collected at 0, 1, 3, 5, and 7 days post-IR using laser capture microdissection. TGFbeta-1 mRNA levels were measured using real-time PCR. To investigate the role of oxygen in the regulation of TGFbeta-1, we used our previously reported model of perceived hyperoxia where CF (from 5wks old mice) after isolation were cultured at 5%O 2 (physiological pO 2 ) followed by transferring them to 20%O 2 to induce hyperoxic insult. Results & Conclusions. In vivo, a significant increase (p<0.01; n=5) in TGFbeta-1 mRNA was observed at the infarct site already at day 1 post-IR. The levels continued to increase until day 7 post-IR. In vitro, exposure of CF to 20%O 2 hyperoxic insult induced TGFbeta-1 mRNA (p<0.001; n=4) and protein (p<0.01; n=4) expression. Using a TGFbeta-1 promoter-luciferase reporter and DNA binding assays, we collected first evidence that AP-1 and its component Fra2 as major mediators of oxygen-induced TGFbeta-1 expression. Exposure to 20%O 2 resulted in increased localization of Fra2 in nucleus. siRNA-dependent Fra-2 knock-down completely abrogated oxygen-induced TGFbeta1 expression. In conclusion, this study presents first evidence that Fra-2 is involved in inducible TGFbeta1 expression in CF. Fra2 was noted as being central in regulating oxygen-induced TGFbeta-1 expression.s

scholarly journals The Immunomodulatory Effect of the Gut Microbiota in Kidney Disease

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Mingxuan Chi ◽  
Kuai Ma ◽  
Jing Wang ◽  
Zhaolun Ding ◽  
Yunlong Li ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Gut Microbiota ◽  
Intestinal Microbiota ◽  
Ischemia Reperfusion Injury ◽  
Therapeutic Potential ◽  
Kidney Diseases ◽  
Ischemia Reperfusion ◽  
Intestinal Flora ◽  
Inflammatory Factors ◽  
Renal Diseases

The human gut microbiota is a complex cluster composed of 100 trillion microorganisms, which holds a symbiotic relationship with the host under normal circumstances. Intestinal flora can facilitate the treatment of human metabolic dysfunctions and interact with the intestinal tract, which could influence intestinal tolerance, immunity, and sensitivity to inflammation. In recent years, significant interests have evolved on the association of intestinal microbiota and kidney diseases within the academic circle. Abnormal changes in intestinal microbiota, known as dysbiosis, can affect the integrity of the intestinal barrier, resulting in the bacterial translocation, production, and accumulation of dysbiotic gut-derived metabolites, such as urea, indoxyl sulfate (IS), and p-cresyl sulfate (PCS). These processes lead to the abnormal activation of immune cells; overproduction of antibodies, immune complexes, and inflammatory factors; and inflammatory cell infiltration that can directly or indirectly cause damage to the renal parenchyma. The aim of this review is to summarize the role of intestinal flora in the development and progression of several renal diseases, such as lupus nephritis, chronic kidney disease, diabetic nephropathy, and renal ischemia-reperfusion injury. Further research on these mechanisms should provide insights into the therapeutic potential of regulating intestinal flora and intervening related molecular targets for the abovementioned nephropathy.

scholarly journals CARD3 Promotes Cerebral Ischemia‐Reperfusion Injury Via Activation of TAK1

2020 ◽  
Vol 9 (9) ◽  
Author(s):  
Xiaolin Wu ◽  
Lijin Lin ◽  
Juan‐Juan Qin ◽  
Lifen Wang ◽  
Hao Wang ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Ischemia Reperfusion Injury ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Transforming Growth Factor Β ◽  
Cerebral Stroke ◽  
Dependent Manner ◽  
Cerebral Ischemia Reperfusion Injury ◽  
Domain 3 ◽  
Multiple Signaling

Background Although multiple signaling cascades and molecules contributing to the pathophysiological process have been studied, the treatments for stroke against present targets have not acquired significant clinical progress. Although CARD3 (caspase activation and recruitment domain 3) protein is an important factor involved in regulating immunity, inflammation, lipid metabolism, and apoptosis, its role in cerebral stroke is currently unknown. Methods and Results Using a mouse model of ischemia‐reperfusion (I‐R) injury based on transient blockage of the middle cerebral artery, we have found that CARD3 expression is upregulated in a time‐dependent manner during I‐R injury. Further animal study revealed that, relative to control mice, CARD3‐knockout mice exhibited decreased inflammatory response and neuronal apoptosis, with reduced infarct volume and lower neuropathological scores. In contrast, neuron‐specific CARD3‐overexpressing transgenic (CARD3‐TG) mice exhibited increased I‐R induced injury compared with controls. Mechanistically, we also found that the activation of TAK1 (transforming growth factor‐β–activated kinase 1) was enhanced in CARD3‐TG mice. Furthermore, the increased inflammation and apoptosis seen in injured CARD3‐TG brains were reversed by intravenous administration of the TAK1 inhibitor 5Z‐7‐oxozeaenol. Conclusions These results indicate that CARD3 promotes I‐R injury via activation of TAK1, which not only reveals a novel regulatory axis of I‐R induced brain injury but also provides a new potential therapeutic approach for I‐R injury.

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