Kidney Week

Abstract: TH-PO536

Single-Cell RNA Sequencing Shows How AP-1 Upregulation Affects Different Kidney Cells in the Chronic Progression of Glomerular Diseases

Session Information

• Glomerular Diseases: Omics, Biomarkers, and Tools
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Li, Shuying, Department of Nephrology, Children’s Hospital of Chongqing Medical University, Chongqing, China

Shuying Li

• Chen, Qilin, Department of Nephrology, Children’s Hospital of Chongqing Medical University, Chongqing, China

Qilin Chen, PhD

• Qiu, Li, Department of Nephrology, Children’s Hospital of Chongqing Medical University, Chongqing, China

Li Qiu

Background

Podocytopathies, resulting from podocyte injury, can lead to proteinuria and often progresses to end-stage renal disease, significantly impacting patient prognosis. Current studies have found that podocyte injury triggers parietal epithelial cell (PEC) activation, proliferation, migration to the capillary tuft, and acquisition of a podocyte phenotype. This process ultimately leads to global glomerulosclerosis and loss of renal function. However, the molecular mechanism underlying this critical process remains unclear.

Methods

We have established a cellular atlas of human glomeruli and kidney tissue from patients with glomerular disease, including 10 pediatric cases and 3 control children using scRNA-seq. Additionally, we conducted in vivo experiments with the AP-1 inhibitor T-5224 in an ADR mouse model.

Results

By rapidly enriching human glomeruli, we constructed a human glomerular cell atlas and identified podocytes with high expression of NPHS2 and PLA2R1. We discovered a group of podocytes expressing AP-1-related genes (JUNB, JUN, FOS, and FOSB), designated as AP-1^high podocytes. Their existence was confirmed through immunofluorescence and immunohistochemistry. RNA velocity analysis revealed that AP-1^high had differentiation potential. Similarly, AP-1^high podocytes were also found in the mouse glomerular cell atlas and validated. Reclustering analysis of renal tissue cell atlas from patients with glomerular diseases revealed a group of AP-1^high PECs expressing CCL2 and ICAM1. Remarkably, RNA velocity analysis indicated a tendency for AP-1^high PECs transform into AP-1^high podocytes.Increased expression of AP-1 was observed in connecting tubules, and endothelial cell subsets exhibiting signatures of inflammatory activation linked to chronic kidney disease progression.The critical role of AP-1 was confirmed by treatment with the AP-1 inhibitor T-5224 in mouse model of ADR-induced nephropathy resulting in significant improvement in proteinuria.

Conclusion

Parietal epithelial cells in glomerular diseases are activated and proliferate due to the up-regulation of AP-1, leading to their migration and differentiation into podocytes. The induction and activation of AP-1-related molecules across various cell subsets likely significantly contribute to chronic kidney injury progression and inflammatory activation.