The Biomarker TCONS_00016233 Drives Septic AKI by Targeting the miR-22-3p/AIFM1 Signaling Axis

Pan Zhang; Lei Yi; Siyuan Qu; Jinzhong Dai; Xiaozhou Li; Bohao Liu; Huiling Li; Kai Ai; Peilin Zheng; Shuangfa Qiu; Yijian Li; Yinhuai Wang; Xudong Xiang; Xiangping Chai; Zheng Dong; Dongshan Zhang

doi:10.1016/j.omtn.2019.12.037

The Biomarker TCONS_00016233 Drives Septic AKI by Targeting the miR-22-3p/AIFM1 Signaling Axis

Mol Ther Nucleic Acids. 2020 Mar 6:19:1027-1042. doi: 10.1016/j.omtn.2019.12.037. Epub 2020 Jan 14.

Authors

Pan Zhang¹, Lei Yi², Siyuan Qu³, Jinzhong Dai¹, Xiaozhou Li¹, Bohao Liu¹, Huiling Li⁴, Kai Ai⁵, Peilin Zheng⁶, Shuangfa Qiu¹, Yijian Li⁵, Yinhuai Wang⁵, Xudong Xiang¹, Xiangping Chai¹, Zheng Dong⁷, Dongshan Zhang⁸

Affiliations

¹ Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China; Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
² Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China; Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China; Department of Urology, Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
³ Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
⁴ Department of Ophthalmology, Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
⁵ Department of Urology, Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
⁶ Department of Endocrinology, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China.
⁷ Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China; Department of Cellular Biology and Anatomy, Medical College of Georgia at Georgia Regents University and Charlie Norwood VA Medical Center, Augusta, GA, USA.
⁸ Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China; Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China. Electronic address: dongshanzhang@csu.edu.cn.

Abstract

The prediction of mortality for septic acute kidney injury (AKI) has been assessed by a number of potential biomarkers, including long noncoding RNAs (lncRNAs). However, the validation of lncRNAs as biomarkers, particularly for the early stages of septic AKI, is still warranted. Our results indicate that the lncRNA TCONS_00016233 is upregulated in plasma of sepsis-associated non-AKI and AKI patients, but a higher cutoff threshold (9.5 × 10⁵, copy number) provided a sensitivity of 71.9% and specificity of 89.6% for the detection of AKI. The plasma TCONS_00016233 was highly correlated with serum creatinine, tissue inhibitor metalloproteinase-2 (TIMP-2), insulin-like growth factor binding protein-7 (IGFBP7), interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), C-reactive protein (CRP), and urinary TCONS_00016233. Lipopolysaccharide (LPS) induced the expression of lncRNA TCONS_00016233 via the Toll-like receptor 4 (TLR4)/p38 mitogen-activated protein kinase (MAPK) signal pathway in human renal tubular epithelial (HK-2) cells. Furthermore, TCONS_00016233 mediates the LPS-induced HK-2 cell apoptosis and the expression of IL-1β and TNF-α. Mechanistically, TCONS_00016233 acts as a competing endogenous RNA (ceRNA) to prevent microRNA (miR)-22-3p-mediated downregulation of the apoptosis-inducing factor mitochondrion-associated 1 (AIFM1). Finally, overexpression of TCONS_00016233 is capable of aggravating the LPS- and cecal ligation and puncture (CLP)-induced septic AKI by targeting the miR-22-3p/AIFM1 axis. Taken together, our data indicate that TCONS_00016233 may serve as an early diagnosis marker for the septic AKI, possibly acting as a novel therapeutic target for septic AKI.

Keywords: AIFM1; TCONS_00016233; miR-22-3p; septic AKI.