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Updated: Sep 18, 2025
Rapid Depletion of Renal Macrophages using Human CD59/Intermedilysin Cell Ablation Tool
Published on: May 9, 2025
ALKBH5 induces macrophage activation to promote renal fibrosis via Retnla
Long Zheng1, Wenjun Gao1, Zhenan Zhang1
1Department of Urology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Abstract:
Renal fibrosis is a common pathological endpoint of various chronic kidney diseases. Macrophages play an important role in the pathophysiological process of renal fibrosis. However, the exact function and molecular mechanism of macrophages during renal fibrosis remain unclear. In this study, we found an increased expression of RNA demethylase AlkB Homolog 5 (ALKBH5) in macrophages from the mice with unilateral ureteral obstruction (UUO) and TGF-β treatments bone marrow-derived macrophages. Macrophage-specific ALKBH5 knockout could significantly alleviate renal fibrosis in UUO mice and decrease the infiltration of macrophages in the kidneys. Further studies showed that ALKBH5 deficiency reduced M2a macrophage polarization and the expression of TGF-β1, Arg1, and CD206 both in vivo and in vitro. RNA sequencing indicated that Resistin-like alpha (Retnla) was the downstream target of ALKBH5, and treatment with recombinant Retnla abrogated the effect of ALKBH5 deficiency on renal fibrosis. We conclude that ALKBH5-dependent regulation of macrophage and kidney fibrosis progression through Retnla represents a novel strategy for patients with chronic kidney disease.
Insights
Researchers identified RNA demethylase ALKBH5 as a key driver in kidney fibrosis. Inhibiting ALKBH5 in macrophages reduces fibrosis by downregulating Retnla, offering a potential therapeutic target for chronic kidney disease.
Area of Science:
- Nephrology
- Immunology
- Molecular Biology
Background:
- Renal fibrosis is a common outcome of chronic kidney diseases.
- Macrophages are implicated in renal fibrosis, but their precise role and mechanisms are not fully understood.
Purpose of the Study:
- To investigate the role of RNA demethylase AlkB Homolog 5 (ALKBH5) in macrophage-mediated renal fibrosis.
- To elucidate the molecular mechanisms by which ALKBH5 influences kidney fibrosis progression.
Main Methods:
- Utilized unilateral ureteral obstruction (UUO) mouse models and TGF-β treated bone marrow-derived macrophages.
- Performed macrophage-specific ALKBH5 knockout experiments.
- Conducted RNA sequencing to identify downstream targets of ALKBH5.
Main Results:
- Increased ALKBH5 expression was observed in macrophages during renal fibrosis.
- Macrophage-specific ALKBH5 knockout ameliorated renal fibrosis and reduced macrophage infiltration.
- ALKBH5 deficiency suppressed M2a macrophage polarization and key markers (TGF-β1, Arg1, CD206).
- Resistin-like alpha (Retnla) was identified as a downstream target of ALKBH5, mediating its fibrotic effects.
Conclusions:
- ALKBH5 promotes renal fibrosis by regulating macrophage polarization and function.
- The ALKBH5-Retnla axis in macrophages represents a novel therapeutic target for chronic kidney disease and renal fibrosis.
