Basic Study
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World J Diabetes. Feb 15, 2025; 16(2): 97287
Published online Feb 15, 2025. doi: 10.4239/wjd.v16.i2.97287
Dapagliflozin exerts anti-apoptotic effects by mitigating macrophage polarization via modulation of the phosphoinositide 3-kinase/protein kinase B signaling pathway
Sheng-Xi Xiong, Lin-Juan Huang, Han-Shuang Liu, Xiao-Xiao Zhang, Min Li, Yu-Bing Cui, Chen Shao, Xiao-Lei Hu
Sheng-Xi Xiong, Lin-Juan Huang, Han-Shuang Liu, Xiao-Xiao Zhang, Min Li, Yu-Bing Cui, Xiao-Lei Hu, Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
Chen Shao, Department of Endocrinology, The Second Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
Author contributions: Xiong SX participated in the conceptualization, methodology, investigation and writing, original draft preparation; Xiong SX, Huang LJ, Liu HS, Zhang XX and Cui YB performed the experiments and analyzed the data; Li M and Shao C participated in the investigation and proofreading; Hu XL provided the reagents and participated in the supervision, resources, writing, reviewing, and editing; All the authors read and approved the manuscript.
Supported by the Natural Science Foundation of Anhui Province, No. 2208085MH216; the Major Natural Science and Technology Project of Bengbu Medical College, No. 2020byfy004; and the Scientific Research Program of Anhui Provincial Health Commission, No. AHWJ2023BAc10028.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of Bengbu Medical University, No. [2022] 320.
Institutional animal care and use committee statement: Any article describing a study (basic research) involving animal subjects should be approved by the Bengbu Medical University Laboratory Animal Management and Ethics Committee, No. [2022] 320.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Data sharing statement: The data generated during and/or analyzed during the present study are available from the corresponding author upon 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: Xiao-Lei Hu, PhD, Chief Doctor, Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical University, No. 287 Changhuai Road, Longzihu District, Bengbu 233000, Anhui Province, China. caesar80@163.com
Received: May 27, 2024
Revised: October 13, 2024
Accepted: November 22, 2024
Published online: February 15, 2025
Processing time: 216 Days and 18.8 Hours
Abstract
BACKGROUND

Macrophages are central to the orchestration of immune responses, inflammatory processes, and the pathogenesis of diabetic complications. The dynamic polarization of macrophages into M1 and M2 phenotypes critically modulates inflammation and contributes to the progression of diabetic nephropathy. Sodium-glucose cotransporter 2 inhibitors such as dapagliflozin, which are acclaimed for their efficacy in diabetes management, may influence macrophage polarization, thereby ameliorating diabetic nephropathy. This investigation delves into these mechanistic pathways, aiming to elucidate novel therapeutic strategies for diabetes.

AIM

To investigate the inhibitory effect of dapagliflozin on macrophage M1 polarization and apoptosis and to explore its mechanism of action.

METHODS

We established a murine model of type 2 diabetes mellitus and harvested peritoneal macrophages following treatment with dapagliflozin. Concurrently, the human monocyte cell line cells were used for in vitro studies. Macrophage viability was assessed in a cell counting kit 8 assay, whereas apoptosis was evaluated by Annexin V/propidium iodide staining. Protein expression was examined through western blotting, and the expression levels of macrophage M1 surface markers, inflammatory cytokines, and apoptotic factors were quantified using flow cytometry, enzyme linked immunosorbent assay, and quantitative real-time polymerase chain reaction analyses.

RESULTS

Dapagliflozin attenuated M1 macrophage polarization and mitigated apoptosis in the abdominal macrophages of diabetic mice, evidenced by the downregulation of proapoptotic genes (Caspase 3), inflammatory cytokines [interleukin (IL)-6, tumor necrosis factor-α, and IL-1β], and M1 surface markers (inducible nitric oxide synthase, and cluster of differentiation 86), as well as the upregulation of the antiapoptotic gene BCL2. Moreover, dapagliflozin suppressed the expression of proteins associated with the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway (PI3K, AKT, phosphorylated protein kinase B). These observations were corroborated in vitro, where we found that the modulatory effects of dapagliflozin were abrogated by 740Y-P, an activator of the PI3K/AKT signaling pathway.

CONCLUSION

Dapagliflozin attenuates the polarization of macrophages toward the M1 phenotype, thereby mitigating inflammation and promoting macrophage apoptosis. These effects are likely mediated through the inhibition of the PI3K/AKT signaling pathway.

Keywords: Dapagliflozin; Macrophage polarization; Inflammation; Macrophage apoptosis; Phosphoinositide 3-kinase/protein kinase B signaling pathway

Core Tip: Sodium-glucose cotransporter-2 inhibitors, a new type of hypoglycemic drug, are widely used in clinical practice. However, their specific protective mechanism in diabetic kidneys has not been fully elucidated. We induced macrophage polarization and apoptosis in a mouse model of type 2 diabetes mellitus in vitro and treated it with dapagliflozin. Ultimately, our study revealed that dapagliflozin attenuates macrophage M1 polarization and apoptosis, reduces inflammatory responses, thereby protecting the kidney, and is associated with the inhibition of the phosphoinositide 3-kinase/protein kinase B signaling pathway.