Dendritic Cells Have a Pro-Fibrotic Transcriptional Profile in UUO and Contribute to Renal Fibrosis in Nx5/6

Le résumé fourni par la source

Introduction: The recruitment/activation of immune cells, like macrophages (Mo) and dendritic cells (DCs), represent key mechanisms in the inflammatory stages leading to fibrosis during the progression of chronic kidney disease (CKD). Mo have been described to modulate kidney tissue damage and repair during the fibrotic process. However, the role of DCs in the early programming of the extracellular matrix deposit has not been established in depth. Hypothesis: We hypothesized that renal DCs are required for the development of early renal fibrosis and display a distinct profibrotic transcriptional profile compared with renal Mo. Methodology: Male CD11c.DOG mice (8–12 weeks, n=4–6) underwent Sham surgery, Unilateral Ureteral Obstruction (UUO, 7 days) or 5/6 nephrectomy (Nx5/6, 5 days). DC depletion in CD11c.DOG mice was induced by diphtheria toxin (8 ng/g/day, i.p.). Wild-type (WT) mice were subjected to UUO to isolate renal DCs (rDCs, CD11c + F4/80 - ) and renal Mo (rMo, CD11c + F4/80 + ) by magnetic separation for gene expression analysis. In both models, renal fibrosis was quantified by Masson’s Trichrome or Picrosirius Red Staining (PSR); Immune cell populations were assessed by flow cytometry and mRNA abundance was analyzed by qPCR. Results: In WT mice, UUO increased renal fibrosis (0.1165% vs 1.002% in UUO; p< 0.001) and renal mRNA abundance of NGAL, CD80 and CD86, two markers of DC activation (p< 0.05). rDCs isolated from UUO animals exhibited higher (p< 0.05) mRNA abundance of NGAL (2.12-fold change), Col1a1 (3.46-fold change) and Col3a1 (3,17-fold change), while rMo showed no significant differences compared with Sham mice. To assess whether DCs contribute to fibrosis, CD11c.DOG mice were used. DC depletion did not prevent tubular dilation or interstitial fibrosis caused by UUO, but it decreased renal NGAL mRNA expression (p< 0.05). Given that this is a severe obstructive injury, we used the Nx5/6 model, which was associated with renal fibrosis and overexpression of Col1a1 (1.71-fold change), Col3a1 (1.37-fold change) and fibronectin-1 (Fn1; 1.62-change fold) mRNA (p< 0.05 vs Sham-Vh). DC depletion in Nx5/6 mice prevented the renal fibrosis by Masson’s Trichrome (3.79% vs 5.80% in Nx5/6-Vh). PSR revealed that this fibrotic response occurred predominantly in the renal medulla (6.80% vs 12.99% in Nx5/6-Vh; p< 0.05), with DC depletion showing a strong trend toward reduced medullary fibrosis (7.61%; p=0.0519). DC depletion also prevented the increase in Col3a1 mRNA (0.93-fold change vs 1.37-fold change in Nx5/6-Vh; p< 0.05) and was associated with lower abundance of Col1a1 and Fn1 (p=0.07 and p=0.09 vs Nx5/6-Vh, respectively), without affecting NGAL or interleukin-6 mRNA levels. Conclusions: DCs contribute to the development of early renal fibrosis in the Nx5/6 model at 5 days, but not in UUO at 7-days. Interestingly, rDCs, and not rMo, exhibit an early profibrotic phenotype characterized by increased extracellular matrix genes and tubular damage in the UUO model. These results suggest that rDCs could actively participate in the initial programming of renal fibrosis, redefining their role within the immune-fibrotic axis in CKD. Funding: Fondecyt #1231909, #11241074, ECOS210024 & FOVI240189. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.