Conformational change in transfer RNA is an early indicator of acute cellular damage.
Tissue damage by oxidative stress is a key pathogenic mechanism in various diseases, including AKI and CKD. Thus, early detection of oxidative tissue damage is important. Using a tRNA-specific modified nucleoside 1-methyladenosine (m1A) antibody, we show that oxidative stress induces a direct conformational change in tRNA structure that promotes subsequent tRNA fragmentation and occurs much earlier than DNA damage. In various models of tissue damage (ischemic reperfusion, toxic injury, and irradiation), the levels of circulating tRNA derivatives increased rapidly. In humans, the levels of circulating tRNA derivatives also increased under conditions of acute renal ischemia, even before levels of other known tissue damage markers increased. Notably, the level of circulating free m1A correlated with mortality in the general population (n=1033) over a mean follow-up of 6.7 years. Compared with healthy controls, patients with CKD had higher levels of circulating free m1A, which were reduced by treatment with pitavastatin (2 mg/d; n=29). Therefore, tRNA damage reflects early oxidative stress damage, and detection of tRNA damage may be a useful tool for identifying organ damage and forming a clinical prognosis.
Division of Nephrology, Endocrinology, and Vascular Medicine.
Eikan
E
Mishima
Department of Clinical Pharmacology and Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Shizuoka, Japan;
Chisako
C
Inoue
Laboratory of Oncology, Pharmacy Practice and Sciences and.
Daisuke
D
Saigusa
Medical Informatics Center of Tohoku University Hospital, Sendai, Japan;
Ryusuke
R
Inoue
Division of Cardiovascular Surgery.
Koki
K
Ito
Division of Cardiovascular Surgery.
Yusuke
Y
Suzuki
Laboratory of Oncology, Pharmacy Practice and Sciences and.
Daisuke
D
Jinno
Laboratory of Oncology, Pharmacy Practice and Sciences and.
Yuri
Y
Tsukui
Department of Neurosurgery.
Yosuke
Y
Akamatsu
Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan;
Masatake
M
Araki
Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan;
Kimi
K
Araki
Department of Molecular Hematology.
Ritsuko
R
Shimizu
Department of Pharmacy, Kyoto University Hospital, Kyoto, Japan;
Haruka
H
Shinke
Division of Nephrology, Endocrinology, and Vascular Medicine.
Takehiro
T
Suzuki
Division of Nephrology, Endocrinology, and Vascular Medicine.
Yoichi
Y
Takeuchi
Division of Nephrology, Endocrinology, and Vascular Medicine.
Hisato
H
Shima
Division of Nephrology, Endocrinology, and Vascular Medicine.
Yasutoshi
Y
Akiyama
Division of Nephrology, Endocrinology, and Vascular Medicine.
Takafumi
T
Toyohara
Division of Nephrology, Endocrinology, and Vascular Medicine.
Chitose
C
Suzuki
Division of Cardiovascular Surgery.
Yoshikatu
Y
Saiki
Department of Neurosurgery.
Teiji
T
Tominaga
Division of Transplantation, Reconstruction and Endoscopic Surgery, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan;
Shigehito
S
Miyagi
Division of Transplantation, Reconstruction and Endoscopic Surgery, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan;
Naoki
N
Kawagisihi
Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan;
Tomoyoshi
T
Soga
Hygiene and Public Health, Teikyo University School of Medicine, Tokyo, Japan;
Takayoshi
T
Ohkubo
Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan;
Kenichi
K
Yamamura
Department of Planning for Drug Development and Clinical Evaluation, Tohoku University Graduate School of Pharmaceutical Sciences, Aoba-ku, Sendai, Japan;
Yutaka
Y
Imai
Department of Pharmacy, Kyoto University Hospital, Kyoto, Japan;
Satohiro
S
Masuda
Renal Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and.
Venkata
V
Sabbisetti
Renal Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and.
Takaharu
T
Ichimura
Renal Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and.
David B
DB
Mount
Renal Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and.
Joseph V
JV
Bonventre
Division of Nephrology, Endocrinology, and Vascular Medicine.
Sadayoshi
S
Ito
Laboratory of Oncology, Pharmacy Practice and Sciences and.
Yoshihisa
Y
Tomioka
Department of Clinical Pharmacology and Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Shizuoka, Japan;
Kunihiko
K
Itoh
Division of Nephrology, Endocrinology, and Vascular Medicine, Department of Clinical Biology and Hormonal Regulation, and Department of Medical Science, Tohoku University Graduate School of Biomedical Engineering, Sendai, Japan takaabe@med.tohoku.ac.jp.
Takaaki
T
Abe
D058186:Acute Kidney Injury / Q000175:diagnosis / Q000378:metabolism; D000241:Adenosine / Q000031:analogs & derivatives / Q000276:immunology; D000368:Aged; D000818:Animals; D017209:Apoptosis; D016022:Case-Control Studies; D004249:DNA Damage; D005260:Female; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D008968:Molecular Conformation; D018384:Oxidative Stress; D012343:RNA, Transfer / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D017208:Rats, Wistar; D051436:Renal Insufficiency, Chronic / Q000378:metabolism* / Q000401:mortality
C002230:1-methyladenosine; D012343:RNA, Transfer; D000241:Adenosine