Exosomal miR-125b-5p deriving from mesenchymal stem cells promotes tubular repair by suppression of p53 in ischemic acute kidney injury

Cao, Jun; Wang, Bin; Tang, Tao-Tao; Wen, Yi; Li, Zuo‐Lin; Feng, Songtao; Wu, Min; Liú, Dan; Yin, Di; Ma, Kun-Ling; Tang, Ri‐Ning; Wu, Qiuli; Lan, Hui‐Yao; Lv, Lin‐Li; Liu, Bi‐Cheng

doi:10.7150/thno.54550

Cited by 158 publications

(114 citation statements)

References 55 publications

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“…Our previous research has confirmed the above phenomena and verified that autophagy activation could reduce SAKI (15). The role of p53 in SAKI is rarely reported, although previous studies have explored the damaging role of p53 in bilateral renal ischemia-reperfusion induced AKI and cisplatin nephrotoxic AKI (27,28). Other literature has suggested that acetylated p53 may cause damage to myocardial cells (29), liver cells (30), and neurons (31) under septic conditions by promoting apoptosis.…”

Section: Discussionsupporting

confidence: 76%

p53 Deacetylation Alleviates Sepsis-Induced Acute Kidney Injury by Promoting Autophagy

Sun

Mao

et al. 2021

Front. Immunol.

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Recent studies have shown that autophagy upregulation can attenuate sepsis-induced acute kidney injury (SAKI). The tumor suppressor p53 has emerged as an autophagy regulator in various forms of acute kidney injury (AKI). Our previous studies showed that p53 acetylation exacerbated hemorrhagic shock-induced AKI and lipopolysaccharide (LPS)-induced endothelial barrier dysfunction. However, the role of p53-regulated autophagy in SAKI has not been examined and requires clarification. In this study, we observed the dynamic changes of autophagy in renal tubular epithelial cells (RTECs) and verified the protective effects of autophagy activation on SAKI. We also examined the changes in the protein expression, intracellular distribution (nuclear and cytoplasmic), and acetylation/deacetylation levels of p53 during SAKI following cecal ligation and puncture (CLP) or LPS treatment in mice and in a LPS-challenged human RTEC cell line (HK-2 cells). After sepsis stimulation, the autophagy levels of RTECs increased temporarily, followed by a sharp decrease. Autophagy inhibition was accompanied by an increased renal tubular injury score. By contrast, autophagy agonists could reduce renal tubular damage following sepsis. Surprisingly, the expression of p53 protein in both the renal cortex and HK-2 cells did not significantly change following sepsis stimulation. However, the translocation of p53 from the nucleus to the cytoplasm increased, and the acetylation of p53 was enhanced. In the mechanistic study, we found that the induction of p53 deacetylation, due to either the resveratrol/quercetin -induced activation of the deacetylase Sirtuin 1 (Sirt1) or the mutation of the acetylated lysine site in p53, promoted RTEC autophagy and alleviated SAKI. In addition, we found that acetylated p53 was easier to bind with Beclin1 and accelerated its ubiquitination-mediated degradation. Our study underscores the importance of deacetylated p53-mediated RTEC autophagy in future SAKI treatments.

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Section: Discussionsupporting

confidence: 76%

p53 Deacetylation Alleviates Sepsis-Induced Acute Kidney Injury by Promoting Autophagy

Sun

Mao

et al. 2021

Front. Immunol.

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“…MicroRNAs (miRNAs/miRs) are a novel class of non-coding small ribonucleic acids, which can regulate gene expression by suppression of mRNA translation or degradation of mRNAs ( 11 , 12 ). Moreover, miRNAs participate in cellular process, including the growth of renal tubular epithelial cells ( 13 , 14 ). Meanwhile, miRNAs have been reported to be associated with AKI progression ( 15 – 17 ).…”

Section: Introductionmentioning

confidence: 99%

“…In recent studies, a number of exosomal proteins, miRNAs and lncRNAs have been reported to promote the progression of AKI. For example, Cao et al ( 14 ) found that exosomal miR-125b-5p deriving from mesenchymal stem cells (MSCs) could promote tubular repair by suppression of p53 in ischemic AKI; Zhang et al ( 23 ) indicated that endothelial progenitor cells-derived exosomal miR-21-5p could alleviate sepsis-induced AKI by inhibiting runt-related transcription factor 1 expression. However, the function of exosomes in AKI needs to be further explored.…”

Section: Introductionmentioning

confidence: 99%

“…On the other hand, MSCs, characterized by the abilities of self-renewal, differentiation, immunomodulation and trophic support, are essential in regenerative medicine owing to the capacity to create a microenvironment conducive to the repair of injured tissues ( 14 ). Previous studies indicated that exosomes derived from MSCs have been proposed as an alternative to MSC-based therapy for several diseases ( 14 , 25 ). In addition, MSC-derived exosomes are known to be involved in AKI progression.…”

Section: Introductionmentioning

confidence: 99%

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Exosomal‑miR‑1184 derived from mesenchymal stem cells alleviates cisplatin‑associated acute kidney injury

Zhang

Zheng

et al. 2021

Mol Med Rep

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Acute kidney injury (AKI) poses a severe threat to human health. MicroRNAs (miRNAs/miRs) are known to be involved in the progression of AKI; however, the function of miR-1184 in AKI remains unclear. Thus, the aim of the present study was to examine the role of this miRNA in kidney injury. In order to mimic AKI in vitro , HK-2 cells were treated with cisplatin. Bioinformatics analysis was performed to explore the differentially expressed miRNAs in AKI. A Cell Counting Kit-8 assay and flow cytometry were performed to examine cell viability and apoptosis, respectively. mRNA expression levels were detected via reverse transcription-quantitative PCR, and protein levels were investigated by western blot analysis. ELISA was performed to examine the levels of IL-1β and TNF-α in the cell supernatants. The results revealed that miR-1184 expression was downregulated in AKI. Exosomes derived from miR-1184 agomir-treated mesenchymal stem cells (MSCs) significantly reversed cisplatin-induced cell growth inhibition by inhibiting apoptosis. Moreover, forkhead box O4 (FOXO4) was found to be the direct target of miR-1184, and exosomes expressing miR-1184 notably inhibited cisplatin-induced inflammatory responses in HK-2 cells via the mediation of IL-1β and TNF-α. Furthermore, exosomes derived from miR-1184 agomir-treated MSCs significantly induced G 1 phase arrest in HK-2 cells via the regulation of FOXO4, p27 Kip1 and CDK2. In conclusion, the present study demonstrated that exosomal-miR-1184 derived from MSCs alleviates cisplatin-associated AKI. Thus, the findings presented herein may shed new light onto the exploration of novel strategies for the treatment of AKI.

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“…Recently, Cao et al highlighted the important roles of miR-125b-5p enriched in exosomes. They found that the adhesive molecules on exosomes assisted in homing to injured areas and miR-125b-5p targeted p53 to inhibit apoptosis and promote tubular repair [ 111 ].…”

Section: Mesenchymal Stem Cell-derived Exosomes In Kidney Injury Repairmentioning

confidence: 99%

Exosomes: Emerging Therapy Delivery Tools and Biomarkers for Kidney Diseases

Jin

et al. 2021

Stem Cells International

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Exosomes are nanometer-sized small EVs coated with bilayer structure, which are released by prokaryotic and eukaryotic cells. Exosomes are rich in a variety of biologically active substances, such as proteins, nucleotides, and lipids. Exosomes are widely present in various body fluids and cell culture supernatants, and it mediates the physiological and pathological processes of the body through the shuttle of these active ingredients to target cells. In recent years, studies have shown that exosomes from a variety of cell sources can play a beneficial role in acute and chronic kidney disease. In particular, exosomes derived from mesenchymal stem cells have significant curative effects on the prevention and treatment of kidney disease in preclinical trials. Besides, some encapsulated substances are demonstrated to exert beneficial effects on various diseases, so they have attracted much attention. In addition, exosomes have extensive sources, stable biological activity, and good biocompatibility and are easy to store and transport; these advantages endow exosomes with superior diagnostic value. With the rapid development of liquid biopsy technology related to exosomes, the application of exosomes in the rapid diagnosis of kidney disease has become more prominent. In this review, the latest development of exosomes, including the biosynthesis process, the isolation and identification methods of exosomes are systematically summarized. The utilization of exosomes in diagnosis and their positive effects in the repair of kidney dysfunction are discussed, along with the specific mechanisms. This review is expected to be helpful for relevant studies and to provide insight into future applications in clinical practice.

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Exosomal miR-125b-5p deriving from mesenchymal stem cells promotes tubular repair by suppression of p53 in ischemic acute kidney injury

Cited by 158 publications

References 55 publications

p53 Deacetylation Alleviates Sepsis-Induced Acute Kidney Injury by Promoting Autophagy

p53 Deacetylation Alleviates Sepsis-Induced Acute Kidney Injury by Promoting Autophagy

Exosomal‑miR‑1184 derived from mesenchymal stem cells alleviates cisplatin‑associated acute kidney injury

Exosomes: Emerging Therapy Delivery Tools and Biomarkers for Kidney Diseases

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