Kidney Week

Abstract: TH-PO0240

Cross-Species Single-Cell and Spatial Profiling of Kidney Macrophage Identifies Conserved GPNMB+ Lipid-Associated Macrophages Linked to Kidney Fibrosis

Session Information

• CKD: Mechanisms of Injury and Fibrosis - 1
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2203 CKD (Non-Dialysis): Mechanisms

Authors

• Zhu, Jiahao, Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China

Jiahao Zhu

• Xu, Lubin, Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China

Lubin Xu, MD

• Zheng, Xixi, Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China

Xixi Zheng, MD

• Yin, Saifu, Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China

Saifu Yin, PhD

• Huang, Zheng, Chinese Academy of Sciences Beijing Institute of Genomics, Beijing, China

Zheng Huang

• Li, Yun, Chinese Academy of Sciences Beijing Institute of Genomics, Beijing, China

Yun Li

• Sun, Yingxue, Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China

Yingxue Sun, PhD

• Lin, Yitao, Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China

Yitao Lin

• Ma, Yixin, Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China

Yixin Ma

• Yan, Xiwei, Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China

Xiwei Yan

• Li, Jiaying, Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China

Jiaying Li

• Wang, Kaiyue, Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China

Kaiyue Wang, PhD

• Wen, Yubing, Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China

Yubing Wen, MD

• Jiang, Lan, Chinese Academy of Sciences Beijing Institute of Genomics, Beijing, China

Lan Jiang

• Lin, Tao, Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China

Tao Lin, MD, PhD

• Chen, Limeng, Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China

Limeng Chen, MD, PhD

Background

Although macrophages play a crucial role in kidney inflammation and fibrosis, the heterogeneity and cross-species conservation of fibrosis-associated macrophage states remain incompletely elucidated, hindering the development of macrophage-targeted therapies.

Methods

We combined in-house human pan-kidney-disease multi-omic sequencing, including paired single-nucleus RNA (snRNA) and chromatin accessibility (snATAC) profiling of biopsy samples from 208 donors, with an integrated murine injury-to-fibrosis single-cell transcriptomic atlas to map diverse kidney monocyte, macrophage, and dendritic cell (M/DC) states. We constructed human kidney M/DC multi-omic (12,779 nuclei for snRNA, and 10,260 nuclei for snATAC) and murine M/DC (28,313 high-quality cells) atlases across multiple models and timepoints, revealing shared subpopulations. Immunofluorescence on kidney biopsy slices was performed. Furthermore, external bulk RNA sequencing datasets were analyzed for validation.

Results

In mice, recruited Ly6C^hi monocytes bifurcated into an inflammation-related branch and a fibrosis/repairing-associated branch encompassing Gpnmb⁺ and Arg1⁺Fn1⁺ macrophages. Cross-species signature mapping identified human GPNMB⁺ and FN1⁺ macrophages corresponding to murine Gpnmb⁺ and Arg1⁺Fn1⁺ subsets. Single cell pathway analysis (SCPA) revealed that GPNMB⁺ macrophages exhibit a unique lipid- and lysosomes- associated profile compared to other macrophage subsets. Moreover, integrated snRNA and snATAC analysis revealed an MITF-centered cis-regulatory program in GPNMB⁺ macrophages, while spatial transcriptomic and cell-cell communication analyses revealed their localization within fibroblast-enriched niches and their engagement in profibrotic signaling. Additionally, immunofluorescence confirmed the presence of GPNMB⁺CD68⁺ cells across multiple human kidney disease entities. Clinically, high expression of GPNMB⁺ macrophage signature showed the strongest association with kidney function among myeloid cells in our pan-kidney-disease cohort, and predicted graft loss in transplant biopsies from an independent validation cohort.

Conclusion

We first established a cross-species kidney M/DC multi-omic reference and defined conserved GPNMB⁺ lipid-associated macrophages linked to fibrosis, shedding light on novel macrophage-targeted interventions in pan-kidney disease.

Funding

• Government Support – Non-U.S.