Abstract: PO1402
Comparison of Glomerular Proteomics Profiles of Healthy Human Kidney and Minimal Change Disease Identifies Distinct Targets and Pathways
Session Information
- Glomerular Diseases: Fibrosis and Extracellular Matrix
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix
Authors
- Almaani, Salem, The Ohio State University, Columbus, Ohio, United States
- Madhavan, Sethu M., The Ohio State University, Columbus, Ohio, United States
- Shapiro, John P., The Ohio State University, Columbus, Ohio, United States
- Satoskar, Anjali A., The Ohio State University, Columbus, Ohio, United States
- Ayoub, Isabelle, The Ohio State University, Columbus, Ohio, United States
- Rovin, Brad H., The Ohio State University, Columbus, Ohio, United States
- Parikh, Samir V., The Ohio State University, Columbus, Ohio, United States
Background
Minimal change disease (MCD) is a common cause of idiopathic nephrotic syndrome and is characterized by diffuse podocyte foot process effacement. The pathogenesis of MCD remains unclear. We hypothesized that proteomics analysis of glomeruli could identify molecular markers that reflect the pathogenesis of MCD.
Methods
We included formalin-fixed paraffin-embedded kidney biopsies from patients with steroid-sensitive MCD (n=9) and normal donor kidneys (n=4). Glomeruli were isolated using laser capture microdissection and HPLC MS/MS was done using Orbitrap eclipse mass spectrometer. After data normalization, groups were clustered using principal component analysis (PCA) and compared by paired t-tests.
Results
PCA showed separate clustering of healthy glomeruli and MCD samples (Figure 1). Out of the 6729 unique proteins identified in MCD glomeruli, 1088 proteins were significantly differentially expressed compared to controls. Pathway analysis showed upregulation of complement pathway components (C1R, C1S, C1QA, C2, C3, C4A, C4B, C5, C7, C8B, C9) and downregulation of carbohydrate and amino acid metabolic pathway enzymes (FBP1, FBP2, ALDOC, ALDOB, AKR1A1, ALDH4A1, ALDH5A1, ACAT1). MCD glomeruli showed a significant reduction in expression of ECM proteins FREM2, FRAS1, CDHR2. Surprisingly, the expression of podocyte slit diaphragm-associated proteins (SYNPO, NPHS2, CD2AP) was not significantly altered in MCD compared to controls. We did not observe differential expression of MCD associated proteins, KANK, CFL1, CMIP. No peptides from SMPDL3b or ANGPTL4 were identified in MCD glomeruli.
Conclusion
Glomeruli from MCD showed differential proteomic signature compared to healthy human glomeruli. Activation of innate immune pathways including the complement system and loss of extracellular matrix and basement membrane-specific components in glomeruli of MCD are novel observations. The role of these markers in the pathogenesis of MCD needs to be investigated.
Funding
- Clinical Revenue Support