WOFAPS 2025 8th World Congress of Pediatric Surgery

Zixia Li ¹, Gengyu Du ¹, Min Yang ², Ting Chen ¹, Zhen Yuan ³, Xiang Yan ¹, Jia Wei ¹

¹ Department of Urology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
² National Clinical Research Center for Child Health, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
³ Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

[Aims]

This study aimed to investigate the mechanism of Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) in macrophages promoting renal fibrosis in obstructive nephropathy, providing rationale for intervention.

[Methods]

Renal tissue biopsies from patients with obstructive nephropathy and normal controls were collected for immunohistochemistry and immunofluorescence staining. In vivo, unilateral ureteral obstruction (UUO) models were established in Trem2 knockout (Trem2^-/-) mice and C57BL/6J (WT) mice. After successful modelling, transdermal glomerular filtration rate (tGFR) measurement system was used to evaluate real-time renal function in mice. Some WT UUO mice received daily intraperitoneal injections of the TREM2 inhibitory peptide sequence IA9 or vehicle. Renal tissues from both normal and obstructed kidneys were harvested on day 14 after the UUO operation to analyse alterations in renal interstitial fibrosis and macrophage polarization. In vitro, bone marrow-derived macrophages (BMDMs) from WT and Trem2^-/- mice were cultured and stimulated with Interleukin-4 (IL-4) and IL-13, and the β-catenin agonist lithium chloride(LiCl) was administered to Trem2^-/- BMDMs for compensatory treatment. Biomarkers associated with macrophage fibrosis, polarization, proliferation, and migration were analyzed.

[Results]

TREM2 expression was significantly elevated in obstructed kidneys of patients and UUO mice. Immunofluorescence showed that TREM2 was co-localized in macrophages. UUO mice exhibited a marked reduction in GFR compared to sham-operated controls, while Trem2^-/- attenuated GFR decline. RNA-Seq and Gene Ontology (GO) enrichment analysis revealed upregulated Trem2 expression in obstructed kidneys. Trem2^-/- or IA9 administration attenuated renal interstitial fibrosis and M2 macrophage polarization in obstructed kidneys. In vitro, Trem2^-/- suppressed macrophage M2 polarization, proliferation, and migration. Mechanism-wise, Trem2^-/- inhibited β-catenin expression. LiCl restored macrophage polarization, proliferation, and migration, impaired by Trem2 deficiency, via β-catenin activation.

[Conclusions]

TREM2 promotes obstructive nephropathy progression by activating the β-catenin signaling pathway, driving M2 macrophage polarization, proliferation, migration, and fibrogenic gene expression.