Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Aug 15, 2023; 14(8): 1234-1248
Published online Aug 15, 2023. doi: 10.4239/wjd.v14.i8.1234
Potential role of microRNA-503 in Icariin-mediated prevention of high glucose-induced endoplasmic reticulum stress
Bao-Lin Su, Liang-Liang Wang, Liang-You Zhang, Shu Zhang, Qiang Li, Gang-Yi Chen
Bao-Lin Su, Liang-Liang Wang, Liang-You Zhang, Shu Zhang, Qiang Li, Gang-Yi Chen, Department of Nephrology, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou 510405, Guangdong Province, China
Author contributions: Su BL and Chen GY designed the study and interpreted the data; Wang LL and Zhang LY performed all experiments and drafted the manuscript; Zhang S and Li Q collected and analyzed the data; Su BL and Chen GY reviewed the manuscript.
Supported by The First Affiliated Hospital of Guangzhou University of Chinese Medicine Innovation and Strengthening Fund, No. 2019QN14.
Institutional review board statement: The study does not involve human experiments.
Institutional animal care and use committee statement: The study was reviewed and approved by the Animal Care and Use Committee of Guangzhou University of TCM, No. GZTCMF1-2022053. All postoperative animal care and surgical interventions complied with the NIH Guide for Care and Use of Laboratory Animals. All surgery and euthanasia were performed under sodium pentobarbital anesthesia (200 mg/kg) by intraperitoneal injection. Every effort was made to minimize suffering.
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
Data sharing statement: The datasets used or/and analyzed during the current study are available from the corresponding author on reasonable request.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Gang-Yi Chen, MD, Doctor, Department of Nephrology, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, No. 16 Jichang Road, Guangzhou 510405, Guangdong Province, China. gangyichen5001@126.com
Received: April 20, 2023
Peer-review started: April 20, 2023
First decision: June 1, 2023
Revised: June 12, 2023
Accepted: July 7, 2023
Article in press: July 7, 2023
Published online: August 15, 2023
Processing time: 113 Days and 3.5 Hours
Abstract
BACKGROUND

Dysregulated microRNA (miRNA) is crucial in the progression of diabetic nephropathy (DN).

AIM

To investigate the potential molecular mechanism of Icariin (ICA) in regulating endoplasmic reticulum (ER) stress-mediated apoptosis in high glucose (HG)-induced primary rat kidney cells (PRKs), with emphasis on the role of miR-503 and sirtuin 4 (SIRT4) in this process.

METHODS

Single intraperitoneal injection of streptozotocin (65 mg/kg) in Sprague-Dawley rats induce DN in the in vivo hyperglycemic model. Glucose-treated PRKs were used as an in vitro HG model. An immunofluorescence assay identified isolated PRKs. Cell Counting Kit-8 and flow cytometry analyzed the effect of ICA treatment on cell viability and apoptosis, respectively. Real-time quantitative polymerase chain reaction and western blot analyzed the levels of ER stress-related proteins. Dual luciferase analysis of miR-503 binding to downstream SIRT4 was performed.

RESULTS

ICA treatment alleviated the upregulated miR-503 expression in vivo (DN) and in vitro (HG). Mechanistically, ICA reduced HG-induced miR-503 overexpression, thereby counteracting its function in downregulating SIRT4 levels. ICA regulated the miR-503/SIRT4 axis and subsequent ER stress to alleviate HG-induced PRKs injury.

CONCLUSION

ICA reduced HG-mediated inhibition of cell viability, promotion of apoptosis, and ER stress in PRKs. These effects involved regulation of the miR-503/SIRT4 axis. These findings indicate the potential of ICA to treat DN, and implicate miR-503 as a viable target for therapeutic interventions in DN.

Keywords: Icariin; MicroRNA-503; Sirtuin 4; Endoplasmic reticulum stress; Diabetic nephropathy; Kidney damage

Core Tip: Icariin (ICA) has shown promise as a potential therapeutic agent for diabetes mellitus (DM) by regulating the miR-503-5p/sirtuin 4 (SIRT4) axis and subsequent endoplasmic reticulum (ER) stress. This study found that ICA treatment reduced high glucose-induced inhibition of cell viability, promotion of apoptosis, and ER stress in primary rat kidney cells. Mechanistically, ICA inhibited the upregulation of miR-503-5p and subsequently restored SIRT4 levels, thereby alleviating high glucose-induced injury in cells. These findings implicate ICA as a candidate drug for the treatment of DM and miR-503-5p as a potential therapeutic target for this disease.