Kidney Week

Abstract: TH-PO555

Human Kidney Tissue Proteomics Unveils Complement Factor D Involved in the Pathogenesis of Focal Segmental Glomerulosclerosis

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

• Yamaguchi, Sahomi, Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

Sahomi Yamaguchi, MD

• Nakano, Toshiaki, Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

Toshiaki Nakano, MD, PhD

• Setoyama, Daiki, Department of Clinical Chemistry and Laboratory Medicine, Kyushu University Hospital, Fukuoka, Japan

Daiki Setoyama, PhD

• Sonawane, Abhijeet, Brigham and Women's Hospital, Boston, Massachusetts, United States

Abhijeet Sonawane, MSc, PhD

• Iwamoto, Takaki, Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

Takaki Iwamoto, MD

• Singh, Sasha, Brigham and Women's Hospital, Boston, Massachusetts, United States

Sasha Singh

• Aikawa, Masanori, Brigham and Women's Hospital, Boston, Massachusetts, United States

Masanori Aikawa, MD, PhD

• Kunisaki, Yuya, Department of Clinical Chemistry and Laboratory Medicine, Kyushu University Hospital, Fukuoka, Japan

Yuya Kunisaki, MD, PhD

• Kitazono, Takanari, Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

Takanari Kitazono, MD, PhD

Background

Focal segmental glomerulosclerosis (FSGS) is a clinicopathological syndrome manifested with nephrosis resistant to glucocorticoids. Given the fact that FSGS has unfavorable renal prognosis, efficient therapeutic options targeting specific pathways are sought to be developed. The Columbia classification proposed the 5 variants, namely Collapsing, TIP, Cellular, Perihilar and NOS. Differences in their renal prognosis imply distinct underlying molecular mechanisms, which remains unclear. Here, we aimed to explore factors involved in the pathogenesis of FSGS by comprehensive proteomics with human kidney tissues.

Methods

Kidney tissues from a total of 73 individuals including 23 FSGS patients, healthy and disease controls, were subjected to the analysis using LC-MS/MS-enabled proteomics. Immunohistochemistry and the microarray data from the Nephroseq database were used for validation.

Results

Our proteomics platform identified a total of 4,168 proteins from renal tissue specimens. Comparison of FSGS and healthy control groups identified 175 proteins increased in FSGS, which were enriched in the complement pathway and immune responses by Gene Ontology analysis. These results suggest involvement of the complement system as an underlying mechanism. Furthermore, complement factor D (CFD), which activates the alternative complement pathway, was identified to be significantly elevated in the FSGS group compared to disease control groups. Analysis with immunohistochemistry and gene expression from the Nephroseq database confirmed that CFD was produced mainly in glomeruli, where complement cascades are possibly triggered. Next, we extracted proteins specific for the Columbia variants. Gene Ontology analysis with these factors uncovered that complement pathway was enriched in the Cellular and TIP variants, while endoplasmic reticulum, ribosome, and ferroptosis pathways were in the Collapsing variant, suggesting their different pathophysiology.

Conclusion

Our study provided deeper insights into the recently proposed functional association between FSGS and the complement pathway, offering targeted treatment options. Moreover, the variant-specific molecular background in the Columbia classification will enable us to stratify treatments of FSGS.