Kidney Week

Abstract: TH-PO543

Multisystem Alterations in the Mesangium of IgA Nephropathy Mice Using Single-Nucleus RNA Sequencing and Single-Nucleus Assay for Transposase-Accessible Chromatin

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

• Yoon, Soo-Young, Kyung Hee University Hospital, Dongdaemun-gu, Seoul, Korea (the Republic of)

Soo-Young Yoon, MD, PhD

• Kim, Dae Kyu, Kyung Hee University Hospital, Dongdaemun-gu, Seoul, Korea (the Republic of)

Dae Kyu Kim, MD

• Jung, Su Woong, Kyung Hee University Hospital at Gangdong, Gangdong-gu, Seoul, Korea (the Republic of)

Su Woong Jung, MD, PhD

• Kim, Jin Sug, Kyung Hee University Hospital, Dongdaemun-gu, Seoul, Korea (the Republic of)

Jin Sug Kim, MD, PhD

• Moon, Ju young, Kyung Hee University Hospital at Gangdong, Gangdong-gu, Seoul, Korea (the Republic of)

Ju young Moon, MD, PhD

• Hwang, Hyeon Seok, Kyung Hee University Hospital, Dongdaemun-gu, Seoul, Korea (the Republic of)

Hyeon Seok Hwang, MD, PhD

• Jeong, Kyunghwan, Kyung Hee University Hospital, Dongdaemun-gu, Seoul, Korea (the Republic of)

Kyunghwan Jeong, MD, PhD

Background

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. One of the most prominent features of IgAN is mesangial proliferation with deposition of immune complexes. The role of the immune response in the development of IgAN is well-established. However, the genetics and pathways involved are not yet fully understood.

Methods

Mesangium from ddY mice (8 weeks gddY mice, n=3) and control mice (8 weeks Balb/c mice, m=3) were analyzed from three different system-level perspectives: genome level by single-nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq), transcription level by single-nucleus RNA sequencing (snRNA-seq), and metabolic level by in-silico metabolic flux simulation. 'Pdgfrb', 'Pdgfra', 'Fhl2' and 'Itga8' were selected as mesangium-specific marker genes prior to analysis.

Results

The study found that there was a proliferation of cells in IgAN compared to the control, as determined through spatial deconvolution of single-nuclei RNA-seq. The cells in the mesangium were rearranged into three subgroups, including two IgAN-specific subgroups and one control-specific subgroup, each with system-level-specific alterations. From an epigenomic perspective, one of the IgAN-specific subgroups revealed a 'positive regulation of cell adhesion' and 'epithelial cell proliferation' compared to the control-specific subgroup. In transcription profile alteration, two IgAN-specific subgroups revealed either upregulation of immune-associated pathways or energy-associated pathways. Metabolic flux changes affected various metabolic pathways, including 'alanine and aspartate metabolism' and 'purine catabolism'. Three metabolic pathways, namely 'beta-alanine metabolism', 'nucleotide metabolism', and 'pyrimidine catabolism', showed multiple simultaneous alterations on all three system levels.

Conclusion

This study provides insight into the key molecular changes that occur during the development of IgAN-associated glomerular injury, particularly in the mesangium of mice.