Kidney Week

Abstract: TH-OR077

Single-Nucleus Transcriptomic Landscape of IgAN Reveals Severity-Linked Glomerular Cell-State Transitions and a Panglomerular Molecular Signature

Session Information

• Glomerular Diseases: Novel Mechanisms of Injury
  October 22, 2026 | Location: Room 401, Convention Center
  Abstract Time: 05:10 PM - 05:20 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Ko, Ara, Seoul National University Hospital, Jongno-gu, Seoul, Korea (the Republic of)

Ara Ko, MD

• Oh, Jae-ik, Seoul National University Hospital, Jongno-gu, Seoul, Korea (the Republic of)

Jae-ik Oh, MD

• Lee, Jinsun, Seoul National University Hospital, Jongno-gu, Seoul, Korea (the Republic of)

Jinsun Lee, MD

• Ku, Hyunah, Seoul National University College of Medicine, Jongno-gu, Seoul, Korea (the Republic of)

Hyunah Ku, MS

• Kim, Donggun, Seoul National University Hospital, Jongno-gu, Seoul, Korea (the Republic of)

Donggun Kim

• Koh, Jung Hun, Seoul National University College of Medicine, Jongno-gu, Seoul, Korea (the Republic of)

Jung Hun Koh, MD

• Kwon, Jin Kyung, Keimyung University Dongsan Medical Center, Daegu, Korea (the Republic of)

Jin Kyung Kwon, MD

• Kim, Yaerim, Keimyung University Dongsan Medical Center, Daegu, Korea (the Republic of)

Yaerim Kim, MD, PhD

• Park, Sehoon, Seoul National University Hospital, Jongno-gu, Seoul, Korea (the Republic of)

Sehoon Park, MD, PhD

• Kim, Dong Ki, Seoul National University Hospital, Jongno-gu, Seoul, Korea (the Republic of)

Dong Ki Kim, MD, PhD

Background

IgA nephropathy(IgAN) is the most common primary glomerulonephritis worldwide, yet the glomerular cellular basis of disease progression has not been characterized at single-cell resolution in a disease-specific cohort. We performed single-nucleus RNA sequencing(snRNA-seq) on the largest IgAN-dedicated cohort to date.

Methods

snRNA-seq was performed on 377,870 nuclei from 31 IgAN and 14 control biopsies. Patients were stratified into high-risk (n=11) and low-risk (n=20) groups based on eGFR <60mL/min/1.73m² or proteinuria >1 g/g at biopsy. Cell populations were annotated via KPMP reference and resolved into substates across podocyte(POD), parietal epithelial cell(PEC), glomerular endothelial cell(GEC), and mesangial cell(Mes) compartments. Pseudobulk DEG, UCell-based glucocorticoid receptor(GR) target scoring (FKBP5, KLF9, ZBTB16, TSC22D3), MEST-C correlation, and CellChat analysis were performed.

Results

Overall POD, Mes, and GEC proportions did not differ between IgAN and controls, yet pseudotime trajectory revealed consistent shifts toward activated and injured states—PEC toward reactive and fibrotic substates, and Mes bypassing homeostatic toward activated. Within IgAN, late-injured POD, quiescent Mes, and fibrotic PEC further stratified by severity. Pseudobulk DEG identified shared transcriptional suppression including GR targets, profound even in morphologically intact cells—healthy POD and quiescent GEC—indistinguishable between risk groups yet correlating with proteinuria and tubular atrophy independently of MEST-C. CellChat revealed an IgAN-exclusive injury circuit: loss of EGF-EGFR signaling, de novo PDGFB-PDGFRB from activated GEC to mesangium, and periostin-driven Mes-to-POD upregulation forming a self-reinforcing loop.

Conclusion

This dataset defines IgAN glomerular heterogeneity at single-cell resolution, demonstrating that transcriptional changes precede structural deterioration independently of histological grading, alongside a remodeled intercellular circuit as a molecular framework for injury propagation.

Funding

• Government Support – Non-U.S.