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Macrophage Polarization in Renal Fibrosis: A Double-Edged Role in Cellular Injury and Repair

Liang Chen, MD, PhD1, Mei Zhang, MD, PhD2, Wei Liu, MD, PhD ORCID 3*

1 Department of Nephrology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
2 Institute of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
3 Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

DOI: 10.18081/2378-5225/14.163  
Cited by 0

 Article history: Received 15 October 2025 · Revised 12 November 2025 · Accepted 13 December 2025 · Published 01 December 2025

© 2025 Liu, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC BY 4.0). 

CC BY 4.0                                                                                                   

Abstract

Background: Renal fibrosis is the final common pathway of chronic kidney disease and is driven by complex interactions between immune cells and renal parenchymal cells. Among immune mediators, macrophages play a central but paradoxical role in both promoting tissue injury and facilitating repair. The dynamic balance between pro-inflammatory and reparative macrophage phenotypes during renal injury remains incompletely understood.

Methods: Renal fibrosis was induced in C57BL/6 mice using the unilateral ureteral obstruction (UUO) model. Macrophage infiltration and polarization were assessed at multiple time points by immunohistochemistry, immunofluorescence, and flow cytometry. Macrophage depletion was achieved using clodronate liposomes, and macrophage polarization was modulated in vivo using lipopolysaccharide or interleukin-4. In vitro, bone marrow–derived macrophages were polarized and their conditioned media applied to renal tubular epithelial cells to evaluate effects on cellular injury and profibrotic signaling. Key inflammatory and fibrotic pathways were analyzed by quantitative PCR and Western blotting.

Results: Macrophage accumulation increased progressively following UUO and correlated with the severity of renal fibrosis. Early injury was characterized by predominant M1 macrophage polarization and activation of NF-κB signaling, accompanied by marked tubular epithelial injury. As fibrosis progressed, M2 macrophages became more abundant and were associated with activation of the TGF-β/Smad pathway and extracellular matrix deposition. Macrophage depletion significantly reduced fibrosis but impaired tubular repair. In vitro, M1 macrophage-derived factors exacerbated epithelial injury, whereas short-term exposure to M2-derived factors promoted repair but induced profibrotic gene expression upon prolonged exposure.

Conclusions: Macrophages exert a dual, context-dependent role in renal fibrosis. While inflammatory macrophages drive early tissue injury, reparative macrophages contribute to both healing and maladaptive fibrogenesis when persistently activated. Therapeutic strategies targeting macrophage polarization, rather than global macrophage suppression, may offer a promising approach for preventing progressive renal fibrosis.

Keywords: Renal fibrosis; Macrophage polarization; M1/M2 macrophages; Unilateral ureteral obstruction; Tubulointerstitial injury; TGF-β/Smad signaling

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BM-Publisher · Pathophysiology of Cell Injury Journal (PCIJ) · E-ISSN 2378-5225 · DOI Prefix 10.18081/pcij/2378-5225

Pathophysiology of Cell Injury Journal (PCIJ)
E-ISSN 2378-5225 · Biannual
BM-Publisher (London, UK)
Open Access

Vol 14, Issue 2 (December 2025), pp. 163–179

How to cite (AMA)

Chen L, Mei M, Liu W. Macrophage Polarization in Renal Fibrosis: A Double-Edged Role in Cellular Injury and Repair. Pathophysiology of Cell Injury Journal (PCIJ). 2025;14(2):163–179. doi: 10.18081/2378-5225/14.163.

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