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preventing renal ischemia reperfusion injury using small interfering

Tatsuki Matsumoto, Madoka Urushido, Haruna Ide, Masayuki Ishihara, Kazu Hamada-Ode, Yoshiko Shimamura, Koji Ogata, Kosuke Inoue, Yoshinori Taniguchi, Takafumi Taguchi, Taro Horino, Shimpei Fujimoto, Yoshio Terada
BACKGROUND: Heat shock protein beta-1 (HSPB1, also known as HSP27) is a small heat shock protein involved in many cellular processes and reportedly protects cells against oxidative stress. Autophagy protects cells from many types of stress and is thought to play a key role in preventing stress in acute kidney injury (AKI). However, little is known about the role of HSPB1 in autophagy and apoptosis in the pathogenesis of AKI. METHODS: We used a rat ischemia/reperfusion AKI model and cultured renal tubular cells as an in vitro model...
2015: PloS One
Bo Lin Chen, Meei Ling Sheu, Keh Sung Tsai, Kuo Cheng Lan, Siao Syun Guan, Cheng Tien Wu, Li Ping Chen, Kuan Yu Hung, Jenq Wen Huang, Chih Kang Chiang, Shing Hwa Liu
AIMS: Renal ischemia-reperfusion (I/R) is a major cause of acute renal failure. The mechanisms of I/R injury include endoplasmic reticulum (ER) stress, inflammatory responses, hypoxia, and generation of reactive oxygen species (ROS). CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) is involved in the ER stress signaling pathways. CHOP is a transcription factor and a major mediator of ER stress-induced apoptosis. However, the role of CHOP in renal I/R injury is still undefined...
November 20, 2015: Antioxidants & Redox Signaling
Christian Herzog, Randy S Haun, Andreas Ludwig, Sudhir V Shah, Gur P Kaushal
Meprin A, composed of α and β subunits, is a membrane-bound metalloproteinase in renal proximal tubules. Meprin A plays an important role in tubular epithelial cell injury during acute kidney injury (AKI). The present study demonstrated that during ischemia-reperfusion-induced AKI, meprin A was shed from proximal tubule membranes, as evident from its redistribution toward the basolateral side, proteolytic processing in the membranes, and excretion in the urine. To identify the proteolytic enzyme responsible for shedding of meprin A, we generated stable HEK cell lines expressing meprin β alone and both meprin α and meprin β for the expression of meprin A...
May 9, 2014: Journal of Biological Chemistry
Takayuki Fujino, Sharifi Muhib, Nobuyuki Sato, Naoyuki Hasebe
p53, a pivotal protein in the apoptotic pathway, has been identified as a mediator of transcriptional responses to ischemia-reperfusion (IR) injury. The characteristics and functional significance of the p53 response in vivo are largely unknown in IR-induced kidney injury. Therapeutic opportunities of delivering small interfering RNA (siRNA) via venous injection have gained recognition; however, systemic adverse effects of siRNA therapy should be considered. To prevent IR-induced kidney injury, we tested the efficacy of transarterial administration of siRNA targeting p53 (p53 siRNA)...
December 1, 2013: American Journal of Physiology. Renal Physiology
A Lau, S Wang, J Jiang, A Haig, A Pavlosky, A Linkermann, Z-X Zhang, A M Jevnikar
Kidney transplant injury occurs with ischemia and alloimmunity. Members of the receptor interacting protein kinase family (RIPK1,3) are key regulators of "necroptosis," a newly recognized, regulated form of necrosis. Necroptosis and apoptosis death appear to be counterbalanced as caspase-8 inhibition can divert death from apoptosis to necrosis. Inhibition of necroptosis in donor organs to limit injury has not been studied in transplant models. In this study, necroptosis was triggered in caspase inhibited tubular epithelial cells (TEC) exposed to tumor necrosis factor alpha in vitro, while RIPK1 inhibition with necrostatin-1 or use of RIPK3(-/-) TEC, prevented necroptosis...
November 2013: American Journal of Transplantation
Daisuke Katagiri, Yoshifumi Hamasaki, Kent Doi, Koji Okamoto, Kousuke Negishi, Masaomi Nangaku, Eisei Noiri
Accumulating evidence of the beyond-glucose lowering effects of a gut-released hormone, glucagon-like peptide-1 (GLP-1), has been reported in the context of remote organ connections of the cardiovascular system. Specifically, GLP-1 appears to prevent apoptosis, and inhibition of dipeptidyl peptidase-4 (DPP-4), which cleaves GLP-1, is renoprotective in rodent ischemia-reperfusion injury models. Whether this renoprotection involves enhanced GLP-1 signaling is unclear, however, because DPP-4 cleaves other molecules as well...
December 2013: Journal of the American Society of Nephrology: JASN
Andrea Havasi, Joseph A Haegele, Jonathan M Gall, Sherry Blackmon, Takaharu Ichimura, Ramon G Bonegio, Maria V Panchenko
HBO1 acetylates lysine residues of histones and is involved in DNA replication and gene transcription. Two isoforms of JADE1, JADE1S and JADE1L, bind HBO1 and promote acetylation of histones in chromatin context. We characterized the role of JADE1-HBO1 complexes in vitro and in vivo during epithelial cell replication. Down-regulation of JADE1 by siRNA diminished the rate of DNA synthesis in cultured cells, decreased endogenous HBO1 protein expression, and prevented chromatin recruitment of replication factor Mcm7, demonstrating that JADE1 is required for cell proliferation...
January 2013: American Journal of Pathology
Yichen Jia, Zitong Zhao, Ming Xu, Tian Zhao, Yongyin Qiu, Yitreen Ooi, Bin Yang, Ruiming Rong, Tongyu Zhu
Endothelin A receptor (ETaR) is a key molecule involved in a variety of biological events such as vessel contraction and inflammatory response in ischemia-reperfusion (I/R) injury. RNA interference using short hairpin RNA (shRNA) is a powerful tool to silence gene expression. Here, the effect of ETaR shRNA on I/R injury in rats was studied. A more effective shRNA sequence out of two constructed into plasmid vectors was selected using the A-10 cell line, and was then applied to a rat model. Twenty-eight male Sprague-Dawley rats were randomized into four groups: Sham, shRNA, vector and phosphate-buffered saline (PBS)...
August 2012: Experimental Biology and Medicine
May M Rabadi, Mei-Chuan Kuo, Tammer Ghaly, Seham M Rabadi, Mia Weber, Michael S Goligorsky, Brian B Ratliff
We aimed to investigate the potential relationship between alarmins [acting via Toll-like receptor-4 (TLR4)], uric acid (UA), and high-mobility group box-1 protein (HMGB1) during acute kidney injury. UA, which is significantly increased in the circulation following renal ischemia-reperfusion injury (IRI), was used both in vitro and in vivo as an early response-signaling molecule to determine its ability to induce the secretion of HMGB1 from endothelial cells. Treatment of human umbilical vein endothelial cells (HUVEC) with UA resulted in increased HMGB1 mRNA expression, acetylation of nuclear HMGB1, and its subsequent nuclear-cytoplasmic translocation and release into the circulation, as determined by Western blotting and immunofluorescence...
March 15, 2012: American Journal of Physiology. Renal Physiology
Xin Wan, Li Fan, Bo Hu, Jing Yang, Xing Li, Xin Chen, Changchun Cao
The transcription factor NF-κB has been found critical to the pathogenesis of renal ischemia-reperfusion injury, which is a major cause of acute kidney injury (AKI). Activation of NF-κB is dependent upon the activation of the specific inhibitory κB kinase (IKK) subunit IKKβ. Here, we investigate whether small interfering RNA (siRNA) targeting IKKβ protects rats from renal ischemia- reperfusion injury in vivo. Renal ischemia-reperfusion injury was induced by clamping the renal artery for 45 min. Rats were treated before ischemia with IKKβ siRNA or scrambled siRNA, administered by renal artery injection...
April 2011: American Journal of Physiology. Renal Physiology
Bin Yang, Sarah A Hosgood, Michael L Nicholson
BACKGROUND: Ischemia-reperfusion injury (IRI) plays key roles in graft viability and posttransplantation function. Caspase-3 associated with apoptosis and inflammation is up-regulated by IRI. We propose that naked small interfering RNA (siRNA) targeting caspase-3 may prevent IRI and improve kidney preservation. METHODS: Porcine kidneys were retrieved after 10-min warm ischemia and flushed with 500 mL hyperosmolar citrate. Caspase-3 siRNA was administered directly into the renal artery in hyperosmolar citrate solution (3 μg/ml) with the renal vein clamped and into autologous blood (0...
March 15, 2011: Transplantation
Biao Feng, Gang Chen, Xiufen Zheng, Hongtao Sun, Xusheng Zhang, Zhu-Xu Zhang, Ying Xiang, Thomas E Ichim, Bertha Garcia, Patrick Luke, Anthony M Jevnikar, Wei-Ping Min
BACKGROUND: Nuclear factor kappaB (NF-kappaB) has been found to be critical to the pathogenesis of renal ischemia-reperfusion injury (IRI). Using small interfering RNA (siRNA) to silence the expression of RelB, a component of the transcription factors Rel/nuclear factor kappaB, may protect renal IRI. Here, we report an siRNA-based treatment of preventing IRI. METHODS: Renal IRI was induced in mice by clamping the left renal pedicle for 25 or 35 min. The therapeutic effects of siRNA were evaluated in renal function, histologic examination, and overall survival after lethal IRI...
May 15, 2009: Transplantation
Xiufen Zheng, Xusheng Zhang, Biao Feng, Hongtao Sun, Motohiko Suzuki, Thomas Ichim, Norihiko Kubo, Arthur Wong, Lisa R Min, Marianne E Budohn, Bertha Garcia, Anthony M Jevnikar, Wei-Ping Min
Ischemia/reperfusion (I/R) injury in organ transplantation significantly contributes to graft failure and is untreatable using current approaches. I/R injury is associated with activation of the complement system, leading to the release of anaphylatoxins, such as C5a, and the formation of the membrane attack complex. Here, we report a novel therapy for kidney I/R injury through silencing of the C5a receptor (C5aR) gene using siRNA. Mice were injected with 50 microg of C5aR siRNA 2 days before induction of ischemia...
October 2008: American Journal of Pathology
Martin J Mangino, Tao Tian, Mary Ametani, Susanne Lindell, James H Southard
BACKGROUND: Cytoskeletal degradation occurs in warm renal ischemia and reperfusion and during hypothermia. The purpose of this study was to determine cytoskeletal changes during cold storage preservation injury in renal tubules and to determine whether these changes contribute to the injury. METHODS: Isolated canine renal proximal tubules or their primary epithelial cultures were cold-stored in University of Wisconsin solution and reperfused in vitro to simulate renal cold storage preservation injury...
February 15, 2008: Transplantation
Xiufen Zheng, Xusheng Zhang, Hongtao Sun, Biao Feng, Mu Li, Gang Chen, Costin Vladau, Dong Chen, Motohiko Suzuki, Lisa Min, Weihua Liu, Robert Zhong, Bertha Garcia, Anthony Jevnikar, Wei-Ping Min
BACKGROUND: Ischemia/reperfusion (I/R) injury occurs in clinical kidney transplantation, which results in graft dysfunction and rejection. It has been documented that I/R injury is associated with complement activation and renal cell apoptosis. The purpose of this study was to develop a strategy to prevent I/R injury using small interfering RNA (siRNA) that target complement 3 (C3) and caspase 3 genes. METHODS: siRNA-expression vectors were constructed to target C3 and caspase 3 genes...
December 27, 2006: Transplantation
Xusheng Zhang, Xiufen Zheng, Hongtao Sun, Biao Feng, Gang Chen, Costin Vladau, Mu Li, Dong Chen, Motohiko Suzuki, Lisa Min, Weihua Liu, Bertha Garcia, Robert Zhong, Wei-Ping Min
BACKGROUND: Apoptotic pathways mediated by caspases play a critical role in renal ischemia-reperfusion injury (IRI). Downregulation of the caspase cascade, using small interfering RNA (siRNA) to silence the expression of caspase 3 and caspase 8, may have substantial therapeutic potential for limiting renal injury. METHODS: IRI was induced in mice by clamping of the renal vein and artery for 25 or 35 min at 37 degrees C. Caspase 3 and caspase 8 (caspase 3/8) siRNA was administrated by hydrodynamic injection...
December 27, 2006: Transplantation
C Du, S Wang, H Diao, Q Guan, R Zhong, A M Jevnikar
Renal tubular epithelial cells (TEC) die by apoptosis or necrosis in renal ischemia-reperfusion injury (IRI). Fas/Fas ligand-dependent fratricide is critical in TEC apoptosis, and Fas promotes renal IRI. Therefore, targeting Fas or caspase-8 may have therapeutic potential for renal injury in kidney transplant or failure. RNA silencing by short hairpin RNA (shRNA) is a novel strategy to down-regulate protein expression. Using this approach, silencing of Fas or caspase-8 by shRNA to prevent TEC apoptosis and IRI was evaluated...
October 2006: American Journal of Transplantation
X Zheng, B Feng, G Chen, X Zhang, M Li, H Sun, W Liu, C Vladau, R Liu, A M Jevnikar, B Garcia, R Zhong, W-P Min
The complement system is one of the important mediators of renal ischemia-reperfusion injury (IRI). We hypothesized that efficient silencing of C3, which is the central component on which all complement activation pathways converge, could be achieved using small interfering RNA (siRNA), and that this would result in overall inhibition of complement activation, thereby preventing IRI in kidneys. A series of experiments was conducted, using a mouse model of IRI and vector-delivered C3-specific siRNA. We demonstrated the following: (1) renal expression of C3 increases as a result of IRI; (2) by incorporation into a pRNAT U6...
September 2006: American Journal of Transplantation
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