Dysregulated Protease Homeostasis Defines Primary FSGS

Area of Science:

• Nephrology
• Proteomics
• Molecular Biology

Background:

• Primary focal segmental glomerulosclerosis (pFSGS) lacks specific biomarkers for diagnosis and outcome prediction.
• Circulating permeability factors are implicated in pFSGS pathogenesis.
• Current research aims to identify unique protein signatures in pFSGS serum.

Purpose of the Study:

• To identify disease-specific protein signatures in the serum of pFSGS patients using liquid chromatography-mass spectrometry-based proteomics.
• To investigate the functional role of identified dysregulated proteins in kidney disease models.

Main Methods:

• Serum proteomics analysis via liquid chromatography-mass spectrometry on samples from pFSGS patients, other proteinuric diseases, and healthy controls.
• In vitro studies using immortalized human podocytes and in vivo experiments with zebrafish larvae (knockdown studies).
• Immunofluorescent staining on zebrafish and human kidney biopsies to validate findings.

Main Results:

• Proteomics identified 27 proteins specifically dysregulated in pFSGS, including proteases and protease inhibitors.
• Reduced serum serpin family A member 1 (SERPINA1) was specific to pFSGS, unlike increased urinary SERPINA1 in nephrotic syndromes.
• SERPINA1 knockdown in zebrafish induced proteinuria, edema, and loss of podocyte markers, supporting its role in glomerular injury.

Conclusions:

• Reduced circulating SERPINA1 is a potential biomarker distinguishing pFSGS.
• SERPINA1's decrease may disrupt the protease-antiprotease balance, contributing to podocyte injury in pFSGS.
• SERPINA1 may have compartment-specific functions in glomerular disease pathogenesis.