Emodin ameliorates renal injury and fibrosis via regulating the miR-490-3p/HMGA2 axis

Liulin Wang; Xuerui Wang; Gang Li; Shanshan Zhou; Rui Wang; Qi Long; Min Wang; Liang Li; Hai Huang; Yuanming Ba

doi:10.3389/fphar.2023.1042093

Emodin ameliorates renal injury and fibrosis via regulating the miR-490-3p/HMGA2 axis

Front Pharmacol. 2023 Mar 3:14:1042093. doi: 10.3389/fphar.2023.1042093. eCollection 2023.

Authors

Liulin Wang^{1

2

3}, Xuerui Wang^{4

5

6}, Gang Li^{1

2

3}, Shanshan Zhou^{1

2

3}, Rui Wang^{1

2

3}, Qi Long^{1

2

3}, Min Wang^{1

2

3}, Liang Li^{1

2

3}, Hai Huang^{1

2

3}, Yuanming Ba^{1

2

3}

Affiliations

¹ Hubei Provincial Hospital of Tranditional Chinese Medicine, Wuhan, China.
² Affiliated Hospital of Hubei University of Traditional Chinese Medicine, Wuhan, China.
³ Hubei Provincial Academy of Traditional Chinese Medicine, Wuhan, China.
⁴ Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China.
⁵ Beijing Key Laboratory of Basic Research With Traditional Chinese Medicine on Infectious Diseases, Beijing, China.
⁶ Beijing Institute of Chinese Medicine, Beijing, China.

Abstract

Renal fibrosis is a major pathological feature of chronic kidney disease (CKD). While emodin is reported to elicit anti-fibrotic effects on renal injury, little is known about its effects on microRNA (miRNA)-modulated mechanisms in renal fibrosis. In this study, we established a unilateral ureteral obstruction (UUO) model and a transforming growth factor (TGF)-β1-induced normal rat renal tubular epithelial cell line (NRK-52E) model to investigate the protective effects of emodin on renal fibrosis and its miRNA/target gene mechanisms. Dual-luciferase assay was performed to confirm the direct binding of miRNA and target genes in HEK293 cells. Results showed that oral administration of emodin significantly ameliorated the loss of body weight and the increase in physicochemical parameters, including serum uric acid, creatinine, and urea nitrogen in UUO mice. Inflammatory cytokines, including tumor necrosis factor-α, monocyte chemoattractant protein-1, and interleukin (IL)-1β, but not IL-6, were down-regulated by emodin administration. Emodin decreased the expression levels of TGF-β1 and fibrotic-related proteins, including alpha-smooth muscle actin, Collagen IV, and Fibronectin, and increased the expression of E-cadherin. Furthermore, miR-490-3p was decreased in UUO mice and negatively correlated with increased expression of high migration protein A2 (HMGA2). We further confirmed HMGA2 was the target of miR-490-3p. Transfection of miR-490-3p mimics decreased, while transfection of miR-490-3p inhibitors increased fibrotic-related proteins and HMGA2 expression levels in TGF-β1-induced NRK-52E cells. Furthermore, transfection of miR-490-3p mimics enhanced the anti-fibrotic effects of emodin, while transfection of miR-490-3p inhibitors abolished the protective effects of emodin. Thus, as a novel target of emodin that prevents renal fibrosis in the HMGA2-dependent signaling pathway, miR-490-3p has potential implications in CKD pathology.

Keywords: HMGA2; emodin; inflammatory factor; microRNA; renal fibrosis.

Grants and funding

Hubei Provincial Science and Technology Department 2020 Provincial Science and Technology Major Special Project (NO 2020ACA019). State Administration of Traditional Chinese Medicine (Project No.: National Chinese Medicine Human Education Letter [2022] No. 75).