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      Control release of mitochondria-targeted antioxidant by injectable self-assembling peptide hydrogel ameliorated persistent mitochondrial dysfunction and inflammation after acute kidney injury

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          Abstract

          Persistent mitochondrial injury occurs after acute kidney injury (AKI) and mitochondria-targeted antioxidant Mito-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) (MT) has shown benefits for AKI, but its efficiency is limited by short half-life and side effect in vivo. Self-assembling peptide (SAP) hydrogel is a robust platform for drug delivery. This study aims to develop an SAP-based carrier to slow release MT for enhancing its long-term therapeutic potency on AKI. The KLD with aspartic acid (KLDD) was designed. The microstructure and in vitro release of MT was assayed. The protective role of MT-loaded SAP (SAP-MT) hydrogel on renal mitochondrial injury, tubular apoptosis, and inflammation was evaluated in mice at five days after ischemia-reperfusion injury (IRI). Our results showed that KLDD could self-assemble into cross-linked nanofiber hydrogel and it had lower release rate than free MT and KLD hydrogel. Compared to IRI and free MT mice, SAP-MT mice exerted reduced renal mitochondria-produced ROS (mtROS) and improved mitochondrial biogenesis and architecture. Consequently, SAP-MT mice showed less renal tubular cell apoptosis, kidney injury marker kidney injury molecule-1 (Kim-1) expression, lower level of pro-inflammatory factors expression, and macrophages infiltration than those of IRI and free MT mice. This study suggested that SAP-MT ameliorated IRI due to its extended mitochondrial protection role than free MT and thus improved the long-term outcomes of AKI.

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          Most cited references29

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          Mitochondrial energetics in the kidney

          Mitochondria provide the kidney with energy to remove waste from the blood and regulate fluid and electrolyte balance. This Review discusses how mitochondrial homeostasis is maintained, the changes in mitochondrial energetics that occur in acute kidney injury and diabetic nephropathy, and how targeting mitochondrial energetics might aid the treatment of renal disease.
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            Acute Kidney Injury.

            Acute kidney injury (AKI) is a global public health concern associated with high morbidity, mortality, and healthcare costs. Other than dialysis, no therapeutic interventions reliably improve survival, limit injury, or speed recovery. Despite recognized shortcomings of in vivo animal models, the underlying pathophysiology of AKI and its consequence, chronic kidney disease (CKD), is rich with biological targets. We review recent findings relating to the renal vasculature and cellular stress responses, primarily the intersection of the unfolded protein response, mitochondrial dysfunction, autophagy, and the innate immune response. Maladaptive repair mechanisms that persist following the acute phase promote inflammation and fibrosis in the chronic phase. Here macrophages, growth-arrested tubular epithelial cells, the endothelium, and surrounding pericytes are key players in the progression to chronic disease. Better understanding of these complex interacting pathophysiological mechanisms, their relative importance in humans, and the utility of biomarkers will lead to therapeutic strategies to prevent and treat AKI or impede progression to CKD or end-stage renal disease (ESRD).
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              Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome.

              Dying cells are capable of activating the innate immune system and inducing a sterile inflammatory response. Here, we show that necrotic cells are sensed by the Nlrp3 inflammasome resulting in the subsequent release of the proinflammatory cytokine IL-1beta. Necrotic cells produced by pressure disruption, hypoxic injury, or complement-mediated damage were capable of activating the Nlrp3 inflammasome. Nlrp3 inflammasome activation was triggered in part through ATP produced by mitochondria released from damaged cells. Neutrophilic influx into the peritoneum in response to necrotic cells in vivo was also markedly diminished in the absence of Nlrp3. Nlrp3-deficiency moreover protected animals against mortality, renal dysfunction, and neutrophil influx in an in vivo renal ischemic acute tubular necrosis model. These findings suggest that the inhibition of Nlrp3 inflammasome activity can diminish the acute inflammation and damage associated with tissue injury.
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                Author and article information

                Journal
                Drug Deliv
                Drug Deliv
                IDRD
                idrd20
                Drug Delivery
                Taylor & Francis
                1071-7544
                1521-0464
                2018
                16 February 2018
                : 25
                : 1
                : 546-554
                Affiliations
                Key Laboratory of Transplant Engineering and Immunology, Regenerative Medicine Research Center, West China Hospital, Sichuan University , Chengdu, China
                Author notes

                Supplemental data for this article can be accessed here .

                CONTACT Jingping Liu liujingping@ 123456scu.edu.cn ;
                Yanrong Lu luyanrong@ 123456scu.edu.cn Key Laboratory of Transplant Engineering and Immunology, Regenerative Medicine Research Center, West China Hospital, Sichuan University , No. 1 Keyuan 4th Road, Gaopeng Ave, Chengdu610041, China
                Author information
                http://orcid.org/0000-0001-8364-639X
                Article
                1440445
                10.1080/10717544.2018.1440445
                6058479
                29451033
                eb7effd3-1144-45b3-80f8-2e09f8ace87a
                © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 27 November 2017
                : 06 February 2018
                : 11 February 2018
                Page count
                Pages: 9, Words: 5010
                Funding
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 31200754
                Award ID: 81571808
                Funded by: China Postdoctoral Science Foundation 10.13039/501100002858
                Award ID: 2012M511931
                This work was supported by grants from National Natural Science Foundation of China (31200754, 81571808) and China Postdoctoral Science Foundation (2012M511931).
                Categories
                Research Article

                Pharmacology & Pharmaceutical medicine
                acute kidney injury,mitochondria,mito-tempo,self-assembling peptide,control release

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