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epigenetics in AKI

Shinya Oki, Kenbun Sone, Katsutoshi Oda, Ryuji Hamamoto, Masako Ikemura, Daichi Maeda, Makoto Takeuchi, Michihiro Tanikawa, Mayuyo Mori-Uchino, Kazunori Nagasaka, Aki Miyasaka, Tomoko Kashiyama, Yuji Ikeda, Takahide Arimoto, Hiroyuki Kuramoto, Osamu Wada-Hiraike, Kei Kawana, Masashi Fukayama, Yutaka Osuga, Tomoyuki Fujii
The histone methyltransferase EZH2, a key epigenetic modifier, is known to be associated with human tumorigenesis. However, the physiological importance of EZH2 and its clinical relevance in endometrial cancer remain unclear. Hence, in the present study, we investigated the expression and function of EZH2 in endometrial cancer. In a quantitative real-time PCR analysis of 11 endometrial cancer cell lines and 52 clinical endometrial cancer specimens, EZH2 was significantly overexpressed in cancer cells and tissues compared to that in corresponding normal control cells and tissues...
March 17, 2017: Oncotarget
Kostiantyn Dreval, Aline de Conti, Shinji Furuya, Frederick A Beland, Ivan Rusyn, Igor P Pogribny
Excessive alcohol consumption has a significant impact on human health and is a major public health problem worldwide. One of the consequences of long-term excessive alcohol consumption is cellular injury in almost all organs and tissues, with acute kidney injury (AKI) being one of the most common pathological manifestations. In the present study, using a mouse model of alcoholic liver fibrosis-associated AKI induced by a combined treatment with carbon tetrachloride (CCl4) and ethanol and resembling pathological features of AKI in human alcoholic liver fibrosis, we demonstrate alterations in histone modifications in the kidneys and, importantly, in the promoter region of the over-expressed SRY (sex determining region Y)-box 9 (Sox9) gene...
March 8, 2017: Toxicology
Seiji Yamamoto, Tomoko Hagihara, Yoshiyuki Horiuchi, Akira Okui, Shotaro Wani, Tokuyuki Yoshida, Takao Inoue, Aki Tanaka, Takashi Ito, Yutaka Hirose, Yoshiaki Ohkuma
In eukaryotes, the Mediator complex has important roles in regulation of transcription by RNA polymerase II. Mediator is a large complex with more than 20 subunits that form head, middle, tail and CDK/cyclin modules. Among them, CDK8 and/or CDK19 (CDK8/19), and their counterpart cyclin C, form the CDK/cyclin module together with Mediator subunits MED12 and MED13. Despite evidences of both activation and repression, the precise functional roles of CDK8/19 in transcription are still elusive. Our previous results indicate that CDK8/19 recruits epigenetic regulators to repress immunoresponse genes...
March 2017: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
Olga Ruiz-Andres, Maria Dolores Sanchez-Niño, Juan Antonio Moreno, Marta Ruiz-Ortega, Adrian Mario Ramos, Ana Belen Sanz, Alberto Ortiz
Chronic kidney disease (CKD) is associated to an increased risk of death, CKD progression, and acute kidney injury (AKI) even from early stages, when glomerular filtration rate (GFR) is preserved. The link between early CKD and these risks is unclear, since there is no accumulation of uremic toxins. However, pathological albuminuria and kidney inflammation are frequent features of early CKD, and the production of kidney protective factors may be decreased. Indeed, Klotho expression is already decreased in CKD category G1 (normal GFR)...
December 1, 2016: American Journal of Physiology. Renal Physiology
Björn Tampe, Ulrike Steinle, Désirée Tampe, Julienne L Carstens, Peter Korsten, Elisabeth M Zeisberg, Gerhard A Müller, Raghu Kalluri, Michael Zeisberg
Acute kidney injury (AKI) and progressive chronic kidney disease (CKD) are intrinsically tied syndromes. In this regard, the acutely injured kidney often does not achieve its full regenerative capacity and AKI directly transitions into progressive CKD associated with tubulointerstitial fibrosis. Underlying mechanisms of such AKI-to-CKD progression are still incompletely understood and specific therapeutic interventions are still elusive. Because epigenetic modifications play a role in maintaining tissue fibrosis, we used a murine model of ischemia-reperfusion injury to determine whether aberrant promoter methylation of RASAL1 contributes causally to the switch between physiological regeneration and tubulointerstitial fibrogenesis, a hallmark of AKI-to-CKD progression...
January 2017: Kidney International
Kathy Lee-Son, Jennifer G Jetton
In spite of recent advances in the field of acute kidney injury (AKI) research, morbidity and mortality remain high for AKI sufferers. The study of genetic influences in AKI pathways is an evolving field with potential for improving outcomes through the identification of risk and protective factors at the individual level that may in turn allow for the development of rational therapeutic interventions. Studies of single nucleotide polymorphisms, individual susceptibility to nephrotoxic medications, and epigenetic factors comprise a growing body of research in this area...
March 2016: Journal of Pediatric Genetics
Robert L Chevalier
There is an alarming global increase in the incidence of end-stage kidney disease, for which early biomarkers and effective treatment options are lacking. Largely based on the histology of the end-stage kidney and on the model of unilateral ureteral obstruction, current investigation is focused on the pathogenesis of renal interstitial fibrosis as a central mechanism in the progression of chronic kidney disease (CKD). It is now recognized that cumulative episodes of acute kidney injury (AKI) can lead to CKD, and, conversely, CKD is a risk factor for AKI...
July 1, 2016: American Journal of Physiology. Renal Physiology
Taotao Ma, Cheng Huang, Xiaoming Meng, Xiaofeng Li, Yilong Zhang, Shuai Ji, Jun Li, Min Ye, Hong Liang
Cisplatin, a highly effective and widely used chemotherapeutic agent, has a major limitation for its nephrotoxicity. We recently identified a novel strategy for attenuating its nephrotoxicity in chemotherapy by an effective adjuvant via epigenetic modification through targeting HDAC2. Molecular docking and SPR assay firstly reported that 18βGA, major metabolite of GA, could directly bind to HDAC2 and inhibit the activity of HDAC2. The effects and mechanisms of GA and 18βGA were assessed in CP-induced AKI in C57BL/6 mice, and in CP-treated HK-2 and mTEC cells lines...
2016: Scientific Reports
Tetsuro Kamiya, Aki Goto, Eri Kurokawa, Hirokazu Hara, Tetsuo Adachi
Epithelial-mesenchymal transition (EMT) plays a pivotal role in the progression of cancer, and some transcription factors including Slug and Snail are known to be involved in EMT processes. It has been well established that the excess production of reactive oxygen species (ROS) and epigenetics such as DNA methylation and histone modifications participate in carcinogenesis; however, the cross talk mechanism among EMT, ROS, and epigenetics remains unclear. In the present study, we demonstrated that the treatment of human breast cancer MCF-7 cells with phorbol ester (TPA), a protein kinase C activator, significantly induced cell proliferation and migration, and these were accompanied by the significant induction of Slug expression...
2016: Oxidative Medicine and Cellular Longevity
Mikko Konki, Kalyan Pasumarthy, Maia Malonzo, Annele Sainio, Cristina Valensisi, Mirva Söderström, Maheswara Reddy Emani, Aki Stubb, Elisa Närvä, Bishwa Ghimire, Asta Laiho, Hannu Järveläinen, Riitta Lahesmaa, Harri Lähdesmäki, R David Hawkins, Riikka J Lund
Epigenomic regulation is likely to be important in the maintenance of genomic integrity of human pluripotent stem cells, however, the mechanisms are unknown. We explored the epigenomes and transcriptomes of human pluripotent stem cells before and after spontaneous transformation to abnormal karyotypes and in correlation to cancer cells. Our results reveal epigenetic silencing of Catalase, a key regulator of oxidative stress and DNA damage control in abnormal cells. Our findings provide novel insight into the mechanisms associated with spontaneous transformation of human pluripotent stem cells towards malignant fate...
February 25, 2016: Scientific Reports
Carlos E Palant, Richard L Amdur, Lakhmir S Chawla
Recent controlled trials, epidemiological analyses and basic research studies offer a comprehensive view of the short and long-term clinical repercussion of de novo acute kidney injury or AKI. While most post-AKI patients recover their baseline renal function, a significant number, approximately ~20% of those affected, will go on to develop long term illness characterized by an increase in late stage CKD, cardiovascular complications, and increased death rates. When AKI occurs in hospitalized patients, selected demographic and laboratory results can be incorporated into risk calculators that identify those at higher risk for long-term complications...
2016: Contributions to Nephrology
Aki Yazawa, Yosuke Inoue, Andrew Stickley, Dandan Li, Jianwei Du, Chiho Watanabe
Season of birth (SOB) has been investigated as one of the environmental factors that might epigenetically determine the physiology of individuals. This study investigated the role of SOB in the association between Quality of Life (QOL), a proxy of psychological stress status, and C-reactive protein (CRP) concentration (i.e., inflammatory status) among 1,085 adults (aged 20-57 years old) in Hainan Island, China. High sensitivity CRP concentration was measured in dried blood spot samples, while the abbreviated version of the World Health Organization's QOL questionnaire was used to gather information on six QOL domains...
2015: PloS One
Hitomi Matsuzaki, Eiichi Okamura, Takuya Takahashi, Aki Ushiki, Toshinobu Nakamura, Toru Nakano, Kenichiro Hata, Akiyoshi Fukamizu, Keiji Tanimoto
Genomic imprinting is a major monoallelic gene expression regulatory mechanism in mammals, and depends on gamete-specific DNA methylation of specialized cis-regulatory elements called imprinting control regions (ICRs). Allele-specific DNA methylation of the ICRs is faithfully maintained at the imprinted loci throughout development, even in early embryos where genomes undergo extensive epigenetic reprogramming, including DNA demethylation, to acquire totipotency. We previously found that an ectopically introduced H19 ICR fragment in transgenic mice acquired paternal allele-specific methylation in the somatic cells of offspring, whereas it was not methylated in sperm, suggesting that its gametic and postfertilization modifications were separable events...
November 15, 2015: Development
Daniel Mar, Sina A Gharib, Richard A Zager, Ali Johnson, Oleg Denisenko, Karol Bomsztyk
Aberrant gene expression is a molecular hallmark of acute kidney injury (AKI). As epigenetic processes control gene expression in a cell- and environment-defined manner, understanding the epigenetic pathways that regulate genes altered by AKI may open vital new insights into the complexities of disease pathogenesis and identify possible therapeutic targets. Here we used matrix chromatin immunoprecipitation and integrative analysis to study 20 key permissive and repressive epigenetic histone marks at transcriptionally induced Tnf, Ngal, Kim-1, and Icam-1 genes in mouse models of AKI; unilateral renal ischemia/reperfusion, lipopolysaccharide (LPS), and their synergistically injurious combination...
October 2015: Kidney International
Jinhua Tang, Shougang Zhuang
PURPOSE OF REVIEW: Recent advances in epigenetics indicate the involvement of several epigenetic modifications in the pathogenesis of acute kidney injury (AKI). The purpose of this review is to summarize our understanding of recent advances in the epigenetic regulation of AKI and provide mechanistic insight into the role of acetylation, methylation, and microRNA expression in the pathological processes of AKI. RECENT FINDINGS: Enhancement of protein acetylation by pharmacological inhibition of histone deacetylases leads to more severe tubular injury and impairment of renal structural and functional recovery...
July 2015: Current Opinion in Nephrology and Hypertension
Roxana Rodríguez-Romo, Nathan Berman, Arturo Gómez, Norma A Bobadilla
Epigenetic modifications have emerged as a new, important contributor to gene expression regulation in both normal and pathophysiological conditions. Epigenetics have been studied in many diseases and conditions such as acute kidney Injury (AKI), a syndrome with a high prevalence that carries a poor prognosis with increased morbidity and mortality. In addition, it has recently been shown that AKI increases the risk for the development of chronic kidney disease (CKD). The specific molecular mechanisms by which AKI increases the risk of CKD and end stage renal disease (ESRD) remain unknown, although there is new evidence supporting a role of epigenetic changes...
May 25, 2015: Nephrology
Vinicius Andrade-Oliveira, Mariane T Amano, Matheus Correa-Costa, Angela Castoldi, Raphael J F Felizardo, Danilo C de Almeida, Enio J Bassi, Pedro M Moraes-Vieira, Meire I Hiyane, Andrea C D Rodas, Jean P S Peron, Cristhiane F Aguiar, Marlene A Reis, Willian R Ribeiro, Claudete J Valduga, Rui Curi, Marco Aurelio Ramirez Vinolo, Caroline M Ferreira, Niels Olsen Saraiva Câmara
Short-chain fatty acids (SCFAs) are fermentation end products produced by the intestinal microbiota and have anti-inflammatory and histone deacetylase-inhibiting properties. Recently, a dual relationship between the intestine and kidneys has been unraveled. Therefore, we evaluated the role of SCFA in an AKI model in which the inflammatory process has a detrimental role. We observed that therapy with the three main SCFAs (acetate, propionate, and butyrate) improved renal dysfunction caused by injury. This protection was associated with low levels of local and systemic inflammation, oxidative cellular stress, cell infiltration/activation, and apoptosis...
August 2015: Journal of the American Society of Nephrology: JASN
Shinji Tanaka, Tetsuhiro Tanaka, Masaomi Nangaku
Recent clinical and animal studies have shown that acute kidney injury (AKI), even if followed by complete recovery of renal function, can eventually result in chronic kidney disease (CKD). Renal hypoxia is emerging as a key player in the pathophysiology of the AKI-to-CKD transition. Capillary rarefaction after AKI episodes induces renal hypoxia, which can in turn profoundly affect tubular epithelial cells, (myo)fibroblasts, and inflammatory cells, culminating in tubulointerstitial fibrosis, i.e., progression to CKD...
December 1, 2014: American Journal of Physiology. Renal Physiology
Yasushi Totoki, Akihiko Yoshida, Fumie Hosoda, Hiromi Nakamura, Natsuko Hama, Koichi Ogura, Aki Yoshida, Tomohiro Fujiwara, Yasuhito Arai, Junya Toguchida, Hitoshi Tsuda, Satoru Miyano, Akira Kawai, Tatsuhiro Shibata
Chondrosarcoma is the second most frequent malignant bone tumor. However, the etiological background of chondrosarcomagenesis remains largely unknown, along with details on molecular alterations and potential therapeutic targets. Massively parallel paired-end sequencing of whole genomes of 10 primary chondrosarcomas revealed that the process of accumulation of somatic mutations is homogeneous irrespective of the pathological subtype or the presence of IDH1 mutations, is unique among a range of cancer types, and shares significant commonalities with that of prostate cancer...
September 2014: Genome Research
Aki Fujiwara-Igarashi, Yuko Goto-Koshino, Hiroyuki Mochizuki, Masahiko Sato, Yasuhito Fujino, Koichi Ohno, Hajime Tsujimoto
To investigate the epigenetic regulation of the p16 gene in canine lymphoid tumor cells, its methylation status was examined in four canine lymphoid tumor cell lines. In three canine lymphoid tumor cell lines (CLBL-1, GL-1, and UL-1) with low-level p16 mRNA expression, 20 CpG sites in the promoter region of p16 gene were consistently methylated although all of the CpG sites were not methylated in another cell line (CL-1) and normal lymph node cells. The expression level of p16 mRNA in these three cell lines was restored after cultivation in the presence of a methylation inhibitor, 5-Aza-2'-deoxycitidine, indicating inactivation of p16 gene via hypermethylation...
August 2014: Research in Veterinary Science
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