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J Am Soc Nephrol. 2014 Oct;25(10):2316-26. doi: 10.1681/ASN.2013091001. Epub 2014 May 15.

Conformational change in transfer RNA is an early indicator of acute cellular damage.

Author information

1
Division of Nephrology, Endocrinology, and Vascular Medicine.
2
Department of Clinical Pharmacology and Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Shizuoka, Japan;
3
Laboratory of Oncology, Pharmacy Practice and Sciences and.
4
Medical Informatics Center of Tohoku University Hospital, Sendai, Japan;
5
Division of Cardiovascular Surgery.
6
Department of Neurosurgery.
7
Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan;
8
Department of Molecular Hematology.
9
Department of Pharmacy, Kyoto University Hospital, Kyoto, Japan;
10
Division of Transplantation, Reconstruction and Endoscopic Surgery, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan;
11
Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan;
12
Hygiene and Public Health, Teikyo University School of Medicine, Tokyo, Japan;
13
Department of Planning for Drug Development and Clinical Evaluation, Tohoku University Graduate School of Pharmaceutical Sciences, Aoba-ku, Sendai, Japan;
14
Renal Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and.
15
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.

Abstract

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.

PMID:
24833129
PMCID:
PMC4178440
DOI:
10.1681/ASN.2013091001
[Indexed for MEDLINE]
Free PMC Article

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