tRF-003634 alleviates adriamycin-induced podocyte injury by reducing the stability of TLR4 mRNA

Xiaoqing Gao; Yunyang Qiao; Shanwen Li; Huimin Shi; Gaoting Qu; Jialing Ji; Weihua Gan; Aiqing Zhang

doi:10.1371/journal.pone.0293043

tRF-003634 alleviates adriamycin-induced podocyte injury by reducing the stability of TLR4 mRNA

PLoS One. 2023 Oct 19;18(10):e0293043. doi: 10.1371/journal.pone.0293043. eCollection 2023.

Authors

Xiaoqing Gao¹, Yunyang Qiao¹, Shanwen Li¹, Huimin Shi¹, Gaoting Qu¹, Jialing Ji¹, Weihua Gan¹, Aiqing Zhang²

Affiliations

¹ Department of Pediatric Nephrology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
² Department of Pediatrics, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.

Abstract

Podocyte injury plays a key role in the production of proteinuria and is closely related to the progression of chronic kidney disease (CKD). Alleviating podocyte injury is beneficial to prevent the occurrence and development of CKD. tRNA-derived RNA fragments (tRFs) are associated with podocytes injury processes such as protein binding, cell adhesion, synapses, the actin cytoskeleton. Our previous data showed that tRF-003634 tightly correlated with podocyte injury, while its effect remains unclear. This study aimed to investigate the role of tRF-003634 in podocyte injury and the potential mechanisms. The expression level of tRF-003634, nephrin, podocin and tRF-003634 targeted toll-like receptor 4 (TLR4) in podocytes and kidney tissues were examined by quantitative real-time PCR (qRT-PCR), western blot and immunohistochemistry. The biochemical indices were monitored and renal pathological changes were assessed by hematoxylin and eosin PAS staining. Furthermore, potential target genes of tRF-003634 were screened using high-throughput mRNA sequencing, and then confirmed by RNA pulse-chase analysis. The results showed that tRF-003634 was downregulated in adriamycin (Adr)-induced podocyte injury. Overexpression of tRF-003634 increased the expression of nephrin and podocin in vivo and in vitro and alleviated podocyte injury. Meanwhile, overexpression of tRF-003634 alleviated proteinuria and renal pathological damage. In addition, high-throughput sequencing after overexpression of tRF-003634 showed that TLR4 might be a downstream target gene. tRF-003634 can alleviate podocyte injury by reducing the stability of TLR4 mRNA, possibly by competing with TLR4 mRNA to bind to YTH domain-containing protein 1 (YTHDC1). In conclusion, tRF-003634 was underexpressed in Adr-induced podocyte injury, and its overexpression alleviated podocyte injury in vitro and in vivo by reducing the stability of TLR4 mRNA.

Copyright: © 2023 Gao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Doxorubicin / adverse effects
Doxorubicin / metabolism
Podocytes* / metabolism
Proteinuria / pathology
RNA, Messenger / metabolism
Renal Insufficiency, Chronic* / pathology
Toll-Like Receptor 4 / genetics
Toll-Like Receptor 4 / metabolism

Substances

Doxorubicin
RNA, Messenger
TLR4 protein, human
Toll-Like Receptor 4

Grants and funding

This work was supported by the National Natural Science Foundation of China (Nos. 81970664) to WHG, the Natural Science Foundation of Jiangsu Province (Nos. BK20211385 and Nos.BK20191082) to SWL, the 789 Outstanding Talent Program of SAHNMU (Nos. 789ZYRC202080119, 789ZYRC202090251) and the Pediatric Medical Research Foundation of Jiangsu Medical Association (SYH-32034-0073) to AQZ,and the Pediatric Medical Research Foundation of Jiangsu Medical Association ( SYH-32034-0085) to HMS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.