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Updated: Jul 8, 2025
Comparative Proteomic Analysis of Whole Kidney, Medulla, and Cortical Tubules in Diabetic Pathogenesis of Kidney Injury in Mice
Published on: May 2, 2025
A proteomic atlas of kidney amyloidosis provides insights into disease pathogenesis
Charalampos Charalampous1, Surendra Dasari2, Ellen McPhail3
1Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA.
Abstract:
The mechanisms of tissue damage in kidney amyloidosis are not well described. To investigate this further, we used laser microdissection-mass spectrometry to identify proteins deposited in amyloid plaques (expanded proteome) and proteins overexpressed in plaques compared to controls (plaque-specific proteome). This study encompassed 2650 cases of amyloidosis due to light chain (AL), heavy chain (AH), leukocyte chemotactic factor-2-type (ALECT2), secondary (AA), fibrinogen (AFib), apo AIV (AApoAIV), apo CII (AApoCII) and 14 normal/disease controls. We found that AFib, AA, and AApoCII have the most distinct proteomes predominantly driven by increased complement pathway proteins. Clustering of cases based on the expanded proteome identified two ALECT2 and seven AL subtypes. The main differences within the AL and ALECT2 subtypes were driven by complement proteins and, for AL only, 14-3-3 family proteins (a family of structurally similar phospho-binding proteins that regulate major cellular functions) widely implicated in kidney tissue dysfunction. The kidney AL plaque-specific proteome consisted of 24 proteins, including those implicated in kidney damage (α1 antitrypsin and heat shock protein β1). Hierarchical clustering of AL cases based on their plaque-specific proteome identified four clusters, of which one was associated with improved kidney survival and was characterized by higher overall proteomic content and 14-3-3 proteins but lower levels of light chains and most signature proteins. Thus, our results suggest that there is significant heterogeneity across and within amyloid types, driven predominantly by complement proteins, and that the plaque protein burden does not correlate with amyloid toxicity.
Insights
Kidney amyloidosis shows diverse protein deposits, mainly driven by complement proteins. Subtypes vary, with some AL amyloidosis cases showing better kidney survival linked to specific protein profiles.
Area of Science:
- Nephrology
- Proteomics
- Biochemistry
Background:
- Mechanisms of kidney damage in amyloidosis remain unclear.
- Amyloid plaques consist of deposited proteins, but their specific roles in tissue damage are not fully understood.
Purpose of the Study:
- To identify proteins in amyloid plaques and those overexpressed in specific amyloidosis types.
- To investigate the heterogeneity of protein deposition across and within different kidney amyloidosis subtypes.
- To explore the relationship between plaque proteome and kidney dysfunction or survival.
Main Methods:
- Laser microdissection-mass spectrometry (LMD-MS) was used to analyze protein content in amyloid plaques.
- A large cohort of 2650 amyloidosis cases (AL, AH, ALECT2, AA, AFib, AApoAIV, AApoCII) and controls were studied.
- Proteomic data were analyzed using clustering techniques to identify subtypes and patterns.
Main Results:
- Fibrinogen (AFib), secondary (AA), and apo CII (AApoCII) amyloidosis proteomes were distinct, primarily driven by complement pathway proteins.
- Two ALECT2 and seven AL amyloidosis subtypes were identified based on expanded proteome clustering.
- AL and ALECT2 subtypes showed differences driven by complement proteins and, in AL cases, 14-3-3 family proteins. Kidney AL plaque-specific proteome included proteins like alpha-1-antitrypsin and heat shock protein beta-1.
- Four clusters of AL cases were identified by plaque-specific proteome, with one showing improved kidney survival associated with higher proteomic content and 14-3-3 proteins.
Conclusions:
- Significant heterogeneity exists across and within kidney amyloidosis types, largely influenced by complement proteins.
- The plaque protein burden does not directly correlate with amyloid toxicity.
- Specific proteomic profiles, including 14-3-3 proteins, may be linked to differential kidney outcomes in AL amyloidosis.
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