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Updated: Apr 15, 2026
Analyses of Proteinuria, Renal Infiltration of Leukocytes, and Renal Deposition of Proteins in Lupus-prone MRL/lpr Mice
Published on: June 8, 2022
Label-free quantitative proteomic analysis reveals strong involvement of complement alternative and terminal pathways
Ying Zhang1, Bo Xu2, Naohiko Kinoshita2
1Department of Structural Pathology, Institute of Nephrology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan; Biofluid Biomarker Center (BB-C), Institute for Research Collaboration and Promotion, Niigata University, Niigata, Japan.
Insights
Glomerular sclerosis involves the complement system, specifically the alternative and terminal pathways. Increased TGF-ß1 suggests podocyte apoptosis contributes to this kidney disease progression.
Area of Science:
- Nephrology
- Proteomics
- Immunology
Background:
- Glomerular sclerosis is a common endpoint for various kidney diseases.
- Limited understanding of the proteomic landscape in human glomerular sclerosis.
- Differentiating aging-related changes from disease-specific processes is challenging.
Purpose of the Study:
- To define the proteomic profile of human glomeruli with aging-related sclerosis.
- To investigate the role of complement pathways in glomerular sclerosis.
- To identify key molecular players in sclerosis progression.
Main Methods:
- Laser capture microdissection of human glomeruli (intermediate and advanced sclerosis).
- Label-free quantitative proteomic analysis.
- Immunohistochemical validation.
Main Results:
- Significant increase in membrane attack complex and complement factor B in sclerotic glomeruli.
- Upregulation of transforming growth factor-beta 1 (TGF-ß1) in sclerosis.
- Evidence for involvement of alternative and terminal complement pathways.
Conclusions:
- Proteomic analysis reveals significant involvement of alternative and terminal complement pathways in human glomerulosclerosis.
- Increased TGF-ß1 supports its role in podocyte apoptosis and sclerosis.
- Provides detailed proteomic insights into aging-related glomerular sclerosis.
Abstract:
Since glomerular sclerosis frequently accompanies various glomerular diseases at the end stages, it is challenging to differentiate ubiquitous biological processes underlying this pathology from those critically involved in specific diseases. Furthermore, in-depth proteomic profile of human glomerular sclerosis remains limited. In this study, human glomeruli with intermediate (i-GS) and advanced (GS) sclerotic lesions, which were excluded from specific renal diseases and assumed to be aging-related, were laser captured from macroscopically normal cortex distant from urological carcinoma, and subjected to label-free quantitative proteomic analysis. We explicate an evident increase of membrane attack complex in i-GS and GS with an up-going tendency, which is accompanied by increasing of inhibitory regulators of alternative and terminal pathways. GO annotation and IPA pathway analysis agree to these results. Proteomic findings are validated by immunohistochemical studies which indicate that alternative and terminal pathways are positively involved in the glomerular sclerosis seen in distinct renal diseases. Furthermore, proteomic analysis also demonstrates remarkable increases of complement factor B in GS and TGF-ß1 in both GS and i-GS. Identification of complement factor B implicates that on-site activation of alternative pathway may occur in injured glomeruli and stepwise increase of TGF-ß1 suggests its contribution to the progression of glomerulosclerosis.
Biological Significance:
This study provides in-depth quantitative proteomic profiles of human glomeruli with intermediate and advanced sclerotic lesions. It reveals that the over-expression of alternative and terminal pathway components is significantly involved in human glomerulosclerosis seen in distinct renal diseases. Proteomic identification of the increased TGF-ß1 provides supporting evidence for the role of podocyte apoptosis leading to human glomerulosclerosis.
