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      miR-21 Protects Against Ischemia/Reperfusion-Induced Acute Kidney Injury by Preventing Epithelial Cell Apoptosis and Inhibiting Dendritic Cell Maturation

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          Abstract

          Renal tubular injury and innate immune responses induced by hypoxia contribute to acute kidney injury. Accumulating evidence suggests that miR-21 overexpression protects against kidney ischemia injury. Additionally, miR-21 emerges as a key inhibitor in dendritic cell maturation. Thus, we hypothesized that miR-21 protects the kidney from IR injury by suppressing epithelial cell damage and inflammatory reaction. In this study, we investigated effects of miR-21 and its signaling pathways (PTEN/AKT/mTOR/HIF, PDCD4/NFκ-B) on kidney ischemia/reperfusion (IR) injury in vitro and in vivo. The results revealed that IR increased miR-21, HIF1α, and 2α expression in vivo and in vitro. MiR-21 interacted with HIF1α and 2α through the PTEN/AKT/mTOR pathway. Moreover, inhibition of miR-21 activated PDCD4/NFκ-B pathways, which are critical for dendritic cell maturation. Renal IR triggers local inflammation by inducing the dendritic cell maturation and promoting the secretion of IL-12, IL-6, and TNF-α cytokines. Knockdown of miR-21 intensified the effect of IR on tubular epithelial cell apoptosis and dendritic cell maturation. Our results suggested that IR-inducible miR-21 protects epithelial cells from IR injury via a feedback interaction with HIF (PTEN/AKT/mTOR/HIF/miR-21) and by inhibiting maturation of DCs through the PDCD4/NF-κB pathway. These findings highlight new therapeutic opportunities in AKI.

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          Most cited references47

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          Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21.

          The tumor suppressor PDCD4 is a proinflammatory protein that promotes activation of the transcription factor NF-kappaB and suppresses interleukin 10 (IL-10). Here we found that mice deficient in PDCD4 were protected from lipopolysaccharide (LPS)-induced death. The induction of NF-kappaB and IL-6 by LPS required PDCD4, whereas LPS enhanced IL-10 induction in cells lacking PDCD4. Treatment of human peripheral blood mononuclear cells with LPS resulted in lower PDCD4 expression, which was due to induction of the microRNA miR-21 via the adaptor MyD88 and NF-kappaB. Transfection of cells with a miR-21 precursor blocked NF-kappaB activity and promoted IL-10 production in response to LPS, whereas transfection with antisense oligonucleotides to miR-21 or targeted protection of the miR-21 site in Pdcd4 mRNA had the opposite effect. Thus, miR-21 regulates PDCD4 expression after LPS stimulation.
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            Dendritic-cell control of pathogen-driven T-cell polarization.

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              Identification of a microRNA signature of renal ischemia reperfusion injury.

              Renal ischemia reperfusion injury (IRI) is associated with significant morbidity and mortality. Given the importance of microRNAs (miRNAs) in regulating gene expression, we examined expression profiles of miRNAs following renal IRI. Global miRNA expression profiling on samples prepared from the kidneys of C57BL/6 mice that underwent unilateral warm ischemia revealed nine miRNAs (miR-21, miR-20a, miR-146a, miR-199a-3p, miR-214, miR-192, miR-187, miR-805, and miR-194) that are differentially expressed following IRI when compared with sham controls. These miRNAs were also differently expressed following IRI in immunodeficient RAG-2/common gamma-chain double-knockout mice, suggesting that the changes in expression observed are not significantly influenced by lymphocyte infiltration and therefore define a lymphocyte-independent signature of renal IRI. In vitro studies revealed that miR-21 is expressed in proliferating tubular epithelial cells (TEC) and up-regulated by both cell-intrinsic and -extrinsic mechanisms resulting from ischemia and TGF-beta signaling, respectively. In vitro, knockdown of miR-21 in TEC resulted in increased cell death, whereas overexpression prevented cell death. However, overexpression of miR-21 alone was not sufficient to prevent TEC death following ischemia. Our findings therefore define a molecular fingerprint of renal injury and suggest miR-21 may play a role in protecting TEC from death.
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                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                26 June 2018
                2018
                : 9
                : 790
                Affiliations
                [1] 1Division of Nephrology, Zhongshan Hospital,Fudan University , Shanghai, China
                [2] 2Shanghai Medical Center of Kidney , Shanghai, China
                [3] 3Shanghai Institute of Kidney and Dialysis , Shanghai, China
                [4] 4Shanghai Key Laboratory of Kidney and Blood Purification , Shanghai, China
                [5] 5Hemodialysis Quality Control Center of Shanghai , Shanghai, China
                Author notes

                Edited by: Alexander Staruschenko, Medical College of Wisconsin, United States

                Reviewed by: Hui Y. Lan, The Chinese University of Hong Kong, Hong Kong; Zhanjun Jia, Nanjing Medical University, China

                *Correspondence: Jie Teng teng.jie@ 123456zs-hospital.sh.cn

                This article was submitted to Renal and Epithelial Physiology, a section of the journal Frontiers in Physiology

                †Co-first authors.

                ‡These authors have contributed equally to this work.

                Article
                10.3389/fphys.2018.00790
                6036242
                30013485
                d24a9fa2-4124-48d3-a7f7-61fd7eb84c09
                Copyright © 2018 Song, Zhang, Xu, Lu, Yu, Fang, Hu, Jia, Teng and Ding.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 23 February 2018
                : 06 June 2018
                Page count
                Figures: 8, Tables: 1, Equations: 0, References: 54, Pages: 14, Words: 8349
                Categories
                Physiology
                Original Research

                Anatomy & Physiology
                microrna-21,hypoxia induced factor,dendritic cells,apoptosis,renal injury
                Anatomy & Physiology
                microrna-21, hypoxia induced factor, dendritic cells, apoptosis, renal injury

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