scholarly journals MicroRNAs as Biomarkers and Therapeutic Targets in Inflammation- and Ischemia-Reperfusion-Related Acute Renal Injury

2020 ◽  
Vol 21 (18) ◽  
pp. 6738
Author(s):  
Yueh-Lin Wu ◽  
Hsiao-Fen Li ◽  
Hsi-Hsien Chen ◽  
Heng Lin
Keyword(s):  
Ischemia Reperfusion ◽  
Control Cell ◽  
Cell Communication ◽  
Kidney Injury ◽  
High Morbidity ◽  
Small Noncoding Rnas ◽  
Exosomal Mirnas ◽  
Extracellular Mirnas ◽  
Mediate Cell

Acute kidney injury (AKI), caused mainly by ischemia-reperfusion, sepsis, or nephrotoxins (such as contrast medium), is identified by an abrupt decline in kidney function and is associated with high morbidity and mortality. Despite decades of efforts, the pathogenesis of AKI remains poorly understood, and effective therapies are lacking. MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the posttranscriptional level to control cell differentiation, development, and homeostasis. Additionally, extracellular miRNAs might mediate cell–cell communication during various physiological and pathological processes. Recently, mounting evidence indicates that miRNAs play a role in the pathogenesis of AKI. Moreover, emerging research suggests that because of their remarkable stability in body fluids, microRNAs can potentially serve as novel diagnostic biomarkers of AKI. Of note, our previous finding that miR-494 is rapidly elevated in urine but not in serum provides insight into the ultimate role of urine miRNAs in AKI. Additionally, exosomal miRNAs derived from stem cells, known as the stem cell secretome, might be a potential innovative therapeutic strategy for AKI. This review aims to provide new data obtained in this field of research. It is hoped that new studies on this topic will not only generate new insights into the pathophysiology of urine miRNAs in AKI but also might lead to the precise management of this fatal disease.

scholarly journals miRNAs as Influencers of Cell–Cell Communication in Tumor Microenvironment

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 220 ◽  
Author(s):  
Ilaria Conti ◽  
Gabriele Varano ◽  
Carolina Simioni ◽  
Ilaria Laface ◽  
Daniela Milani ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cell Communication ◽  
Altered Expression ◽  
Regulate Gene Expression ◽  
Small Noncoding Rnas ◽  
Physiological Processes ◽  
Extracellular Mirnas ◽  
Obesity And Cancer ◽  
Posttranscriptional Level

microRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the posttranscriptional level, inducing the degradation of the target mRNA or translational repression. MiRNAs are involved in the control of a multiplicity of biological processes, and their absence or altered expression has been associated with a variety of human diseases, including cancer. Recently, extracellular miRNAs (ECmiRNAs) have been described as mediators of intercellular communication in multiple contexts, including tumor microenvironment. Cancer cells cooperate with stromal cells and elements of the extracellular matrix (ECM) to establish a comfortable niche to grow, to evade the immune system, and to expand. Within the tumor microenvironment, cells release ECmiRNAs and other factors in order to influence and hijack the physiological processes of surrounding cells, fostering tumor progression. Here, we discuss the role of miRNAs in the pathogenesis of multicomplex diseases, such as Alzheimer’s disease, obesity, and cancer, focusing on the contribution of both intracellular miRNAs, and of released ECmiRNAs in the establishment and development of cancer niche. We also review growing evidence suggesting the use of miRNAs as novel targets or potential tools for therapeutic applications.

scholarly journals The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 347 ◽  
Author(s):  
Miguel Fontecha-Barriuso ◽  
Diego Martin-Sanchez ◽  
Julio Manuel Martinez-Moreno ◽  
Maria Monsalve ◽  
Adrian Mario Ramos ◽  
...  
Keyword(s):  
Mitochondrial Biogenesis ◽  
Kidney Diseases ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Pde Inhibitors ◽  
Its Gene ◽  
Attractive Therapeutic Target ◽  
Amp Activated Protein Kinase

Chronic kidney disease (CKD) is one of the fastest growing causes of death worldwide, emphasizing the need to develop novel therapeutic approaches. CKD predisposes to acute kidney injury (AKI) and AKI favors CKD progression. Mitochondrial derangements are common features of both AKI and CKD and mitochondria-targeting therapies are under study as nephroprotective agents. PGC-1α is a master regulator of mitochondrial biogenesis and an attractive therapeutic target. Low PGC-1α levels and decreased transcription of its gene targets have been observed in both preclinical AKI (nephrotoxic, endotoxemia, and ischemia-reperfusion) and in experimental and human CKD, most notably diabetic nephropathy. In mice, PGC-1α deficiency was associated with subclinical CKD and predisposition to AKI while PGC-1α overexpression in tubular cells protected from AKI of diverse causes. Several therapeutic strategies may increase kidney PGC-1α activity and have been successfully tested in animal models. These include AMP-activated protein kinase (AMPK) activators, phosphodiesterase (PDE) inhibitors, and anti-TWEAK antibodies. In conclusion, low PGC-1α activity appears to be a common feature of AKI and CKD and recent characterization of nephroprotective approaches that increase PGC-1α activity may pave the way for nephroprotective strategies potentially effective in both AKI and CKD.

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 Connexin Gap Junctions and Hemichannels in Modulating Lens Redox Homeostasis and Oxidative Stress in Cataractogenesis

Antioxidants ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1374
Author(s):  
Yumeng Quan ◽  
Yu Du ◽  
Yuxin Tong ◽  
Sumin Gu ◽  
Jean X. Jiang
Keyword(s):  
Oxidative Stress ◽  
Gap Junction ◽  
Redox Homeostasis ◽  
Cell Communication ◽  
Underlying Mechanism ◽  
Post Translational Modifications ◽  
Gap Junction Channels ◽  
Mediate Cell ◽  
The Impact

The lens is continuously exposed to oxidative stress insults, such as ultraviolet radiation and other oxidative factors, during the aging process. The lens possesses powerful oxidative stress defense systems to maintain its redox homeostasis, one of which employs connexin channels. Connexins are a family of proteins that form: (1) Hemichannels that mediate the communication between the intracellular and extracellular environments, and (2) gap junction channels that mediate cell-cell communication between adjacent cells. The avascular lens transports nutrition and metabolites through an extensive network of connexin channels, which allows the passage of small molecules, including antioxidants and oxidized wastes. Oxidative stress-induced post-translational modifications of connexins, in turn, regulates gap junction and hemichannel permeability. Recent evidence suggests that dysfunction of connexins gap junction channels and hemichannels may induce cataract formation through impaired redox homeostasis. Here, we review the recent advances in the knowledge of connexin channels in lens redox homeostasis and their response to cataract-related oxidative stress by discussing two major aspects: (1) The role of lens connexins and channels in oxidative stress and cataractogenesis, and (2) the impact and underlying mechanism of oxidative stress in regulating connexin channels.

scholarly journals Inhibition of  a v b 3 integrin impairs adhesion and uptake of tumor-derived small extracellular vesicles

2020 ◽  
Author(s):  
Wanessa Altei ◽  
Bianca Pachane ◽  
Patty K. Santos ◽  
Ligia Ribeiro ◽  
Bong Hwan Sung ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Cell Communication ◽  
Organ Specific ◽  
Breast Cells ◽  
Mediate Cell ◽  
First Time ◽  
Cd63 Expression ◽  
Cell Cell

Abstract Background: Extracellular vesicles (EVs) are lipid-bound particles that are naturally released from cells and mediate cell-cell communication. Integrin adhesion receptors are enriched in small EVs (SEVs) and SEV-carried integrins have been shown to promote cancer cell migration and to mediate organ-specific metastasis; however, how integrins mediate these effects is not entirely clear and could represent a combination of EV binding to extracellular matrix and cells.Methods: To probe integrin role in EVs binding and uptake, we employed a disintegrin inhibitor (DisBa-01) of integrin binding with specificity for avb3 integrin. EVs were purified from MDA-MB-231 cells conditioned media by serial centrifugation method. Isolated EVs were characterized by different techniques and further employed in adhesion, uptake and co-culture experiments.Results: We find that SEVs secreted from MDA-MB-231 breast cancer cells carry avb3 integrin and bind directly to fibronectin-coated plates, which is inhibited by DisBa-01. SEV coating on tissue culture plates also induces adhesion of MDA-MB-231 cells, which is inhibited by DisBa-01 treatment. Analysis of EV uptake and interchange between cells reveals that the amount of CD63-positive EVs delivered from malignant MDA-MB-231 breast cells to non-malignant MCF10A breast epithelial cells is reduced by DisBa-01 treatment. Inhibition of avb3 integrin decreases CD63 expression in cancer cells suggesting an effect on SEV content.Conclusion: In summary, our findings demonstrate for the first time a key role of avb3 integrin in cell-cell communication through SEVs.

scholarly journals Emerging Role of Ferroptosis in the Pathogenesis of Ischemic Stroke: A New Therapeutic Target?

ASN NEURO ◽  
2021 ◽  
Vol 13 ◽  
pp. 175909142110375
Author(s):  
Zhong-Qi Bu ◽  
Hai-Yang Yu ◽  
Jue Wang ◽  
Xin He ◽  
Yue-Ran Cui ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
High Morbidity ◽  
Treatment And Prevention ◽  
Regulated Cell Death ◽  
Programmed Death ◽  
Research Findings

Ischemic stroke is one of the main causes of high morbidity, mortality, and disability worldwide; however, the treatment methods are limited and do not always achieve satisfactory results. The pathogenesis of ischemic stroke is complex, defined by multiple mechanisms; among them, programmed death of neuronal cells plays a significant role. Ferroptosis is a novel type of regulated cell death characterized by iron redistribution or accumulation and increased lipid peroxidation in the membrane. Ferroptosis is implicated in many pathological conditions, such as cancer, neurodegenerative diseases, and ischemia-reperfusion injury. In this review, we summarize current research findings on ferroptosis, including possible molecular mechanisms and therapeutic applications of ferroptosis regulators, with a focus on the involvement of ferroptosis in the pathogenesis and treatment of ischemic stroke. Understanding the role of ferroptosis in ischemic stroke will throw some light on the development of methods for diagnosis, treatment, and prevention of this devastating disease.

scholarly journals Inhibition of  a v b 3 integrin impairs adhesion and uptake of tumor-derived small extracellular vesicles

2020 ◽  
Author(s):  
Wanessa Altei ◽  
Bianca Pachane ◽  
Patty K. Santos ◽  
Ligia Ribeiro ◽  
Bong Hwan Sung ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Cell Communication ◽  
Αvβ3 Integrin ◽  
Organ Specific ◽  
Breast Cells ◽  
Mediate Cell ◽  
First Time ◽  
Cell Cell

Abstract Background: Extracellular vesicles (EVs) are lipid-bound particles that are naturally released from cells and mediate cell-cell communication. Integrin adhesion receptors are enriched in small EVs (SEVs) and SEV-carried integrins have been shown to promote cancer cell migration and to mediate organ-specific metastasis; however, how integrins mediate these effects is not entirely clear and could represent a combination of EV binding to extracellular matrix and cells. Methods: To probe integrin role in EVs binding and uptake, we employed a disintegrin inhibitor (DisBa-01) of integrin binding with specificity for αvβ3 integrin. EVs were purified from MDA-MB-231 cells conditioned media by serial centrifugation method. Isolated EVs were characterized by different techniques and further employed in adhesion, uptake and co-culture experiments. Results: We find that SEVs secreted from MDA-MB-231 breast cancer cells carry αvβ3 integrin and bind directly to fibronectin-coated plates, which is inhibited by DisBa-01. SEV coating on tissue culture plates also induces adhesion of MDA-MB-231 cells, which is inhibited by DisBa-01 treatment. Analysis of EV uptake and interchange between cells reveals that the amount of CD63-positive EVs delivered from malignant MDA-MB-231 breast cells to non-malignant MCF10A breast epithelial cells is reduced by DisBa-01 treatment. Inhibition of αvβ3 integrin decreases CD63 expression in cancer cells suggesting an effect on SEV content. Conclusion: In summary, our findings demonstrate for the first time a key role of αvβ3 integrin in cell-cell communication through SEVs.

Sex differences in renal ischemia-reperfusion injury

2020 ◽  
Vol 319 (2) ◽  
pp. F149-F154
Author(s):  
Adam Hosszu ◽  
Andrea Fekete ◽  
Attila J. Szabo
Keyword(s):  
Sexual Dimorphism ◽  
Reperfusion Injury ◽  
Sex Hormones ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Ischemia ◽  
Renal Diseases ◽  
High Morbidity ◽  
Renal Ischemia Reperfusion Injury

Ischemia-reperfusion injury of the kidney is caused by the sudden and temporary obstruction of blood flow to the organ. Renal ischemia-reperfusion injury is associated with high morbidity and mortality, but effective therapies are lacking. Sexual dimorphism in renal injury has been acknowledged since the 1940s, and the possible role of sex hormones has been intensively investigated in the past decades. Clinical and experimental data demonstrate sexual differences in renal anatomy, physiology, and susceptibility to renal diseases including but not limited to ischemia-reperfusion injury. Some data suggest the protective role of female sex hormones, whereas others highlight the detrimental effect of male hormones in renal ischemia-reperfusion injury. Although the important role of sex hormones is evident, the exact underlying mechanisms remain to be elucidated. This review focuses on collecting the current knowledge about sexual dimorphism of renal ischemia-reperfusion injury, with emphasis on molecular mechanisms and potential novel therapeutic strategies.

Abstract 494: P21 Plays a Protective Role Against Renal Ischemia Reperfusion Injury and is an Essential Factor for Ischemic Preconditioning

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Satoshi Nishioka ◽  
Daisuke Nakano ◽  
Kento Kitada ◽  
Hiroyuki Ohosaki ◽  
Tadashi Sofue ◽  
...  
Keyword(s):  
Ischemic Preconditioning ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Protective Role ◽  
Renal Ischemia ◽  
Histological Changes ◽  
Sham Surgery ◽  
Life Threatening

Background: We previously reported that various pathological conditions including high blood pressure increase p21 expression in the kidney; however, the functional importance of renal p21 up-regulation has not been clarified yet. In the present study, we evaluated the role of p21 in acute kidney injury, a life-threatening disease that can occur independently of the pathological background of patients (whether renal p21 is up-regulated or not). Methods and Results: The mice lacking functional p21 (p21-KO, n=9) and its wild-type control (WT, n=7) underwent a 45-min renal ischemia followed by a 24-h reperfusion (I/R). I/R significantly increased both mRNA expression and nuclear immunoreactivity of p21 in the kidney of WT compared with sham surgery (p21/β-actin, 1.28±0.23 vs. 0.57±0.15, respectively, P<0.05). I/R injury analyzed by blood urea nitrogen (BUN) and kidney histological changes were exacerbated in p21-KO mice (BUN: WT; 103.8±4.6 mg/dL, p21-KO; 127.7±5.2 mg/dL, P<0.05). The results suggest that p21 plays a protective role against I/R injury. Therefore, we next examined whether p21 is also associated with the protective effect of ischemic preconditioning (IPC), which is an established method of attenuating the I/R injury. IPC (4 sets of a 5-min ischemia and a 5-min reperfusion) clearly improved the I/R injury in WT (BUN: sham; 87.7±22.0 mg/dL, IPC; 39.0±2.3 mg/dL, n=3 and n=7, respectively, P<0.05), whereas there was no difference in the I/R injury in p21-KO mice (BUN: sham; 136.5±13.6 mg/dL, IPC; 127.9±6.9 mg/dL, n=5 and n=8, respectively). IPC increased the renal expression of p21 prior to I/R compared with sham surgery (p21/β-actin: 1.07±0.08 vs. 0.26±0.05 fold, respectively, P<0.05). Conclusion: Renal p21 plays a protective role against I/R injury and is necessary for the beneficial effect of renal IPC.

Loss of clusterin expression worsens renal ischemia-reperfusion injury

2010 ◽  
Vol 298 (3) ◽  
pp. F568-F578 ◽  
Author(s):  
Wenjun Zhou ◽  
Qiunong Guan ◽  
Chris C. H. Kwan ◽  
Huifang Chen ◽  
Martin E. Gleave ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Clinical Care ◽  
Kidney Injury ◽  
Protective Role ◽  
Experimental Models ◽  
Novel Therapy ◽  
Clusterin Expression

Prevention of ischemia-reperfusion injury (IRI) is a challenge in clinical care of the patients with kidney transplants or acute kidney injury, and understanding of the intrinsic mechanisms of resistance to injury in the kidney will lead to a novel therapy. Clusterin, a secreted glycoprotein, is an antiapoptotic protein in cancer cells. Our study is to investigate the role of clusterin in renal IRI. Renal IRI in mice was induced by clamping renal vein and artery for 45 or 50 min at 32°C. Apoptosis of renal tubular epithelial cells (TECs) was determined by FACS analysis. Clusterin expression was examined by Western blot or immunohistochemistry. Here, we showed that clusterin protein was induced in TECs following IRI, and more tubules expressed clusterin in the kidneys following ischemia at higher temperatures. In human proximal TEC HKC-8 cultures, clusterin was upregulated by removal of serum and growth factors in medium and was downregulated by TNF-α-IFN-γ mixture. The levels of clusterin were positively correlated with cell survival in these conditions. Knockdown or knockout of clusterin expression enhanced the sensitivity of TECs to apoptosis. In experimental models of renal IRI, deficiency in clusterin expression worsened the injury, as indicated by a significant increase in renal tissue damage with higher levels of serum creatinine and blood urea nitrogen and by a poorer recovery from the injury in clusterin-deficient mice compared with wild-type mice. Our data indicate that the reduction of inducible expression of clusterin results in an increase in TEC apoptosis in the cultures and renders mice susceptibility to IRI, implying a protective role of clusterin in kidney injury.

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