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Matrix Metalloproteinase-7 in Urinary Extracellular Vesicles Identifies Rapid Disease Progression in Autosomal
Martijn H van Heugten1, Charles J Blijdorp1, Sita Arjune2,3,4
1Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
Insights
Matrix metalloproteinase 7 (MMP-7) in urinary extracellular vesicles (uEVs) shows promise as a biomarker for predicting rapid disease progression in autosomal dominant polycystic kidney disease (ADPKD). This finding could aid in early diagnosis and treatment selection for ADPKD patients.
Area of Science:
- Nephrology
- Biomarker Discovery
- Genetics
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) lacks early biomarkers for disease progression.
- Identifying such markers is crucial for patient counseling and guiding kidney-protective therapies.
Purpose of the Study:
- To identify novel biomarkers for rapid disease progression in ADPKD.
- To investigate urinary extracellular vesicles (uEVs) as a source for these biomarkers.
Main Methods:
- Proteomic analysis of uEVs from ADPKD patients with rapid versus stable disease progression.
- Validation using immunoblotting and ELISA.
- Single-nucleus RNA sequencing to determine the cellular origin of identified biomarkers.
Main Results:
- Matrix metalloproteinase 7 (MMP-7) abundance was significantly higher in uEVs of rapid progressors.
- MMP-7 levels in uEVs, but not whole urine, correlated with disease progression.
- MMP-7 expression was elevated in profibrotic proximal tubule and thick ascending limb cells in ADPKD kidneys.
Conclusions:
- Urinary extracellular vesicle-associated MMP-7 is a promising biomarker for predicting rapid ADPKD progression.
- MMP-7's cellular origin in kidney tubules supports its biological relevance.
- This discovery may lead to improved monitoring and therapeutic strategies for ADPKD.
Significance Statement:
There is an unmet need for biomarkers of disease progression in autosomal dominant polycystic kidney disease (ADPKD). This study investigated urinary extracellular vesicles (uEVs) as a source of such biomarkers. Proteomic analysis of uEVs identified matrix metalloproteinase 7 (MMP-7) as a biomarker predictive of rapid disease progression. In validation studies, MMP-7 was predictive in uEVs but not in whole urine, possibly because uEVs are primarily secreted by tubular epithelial cells. Indeed, single-nucleus RNA sequencing showed that MMP-7 was especially increased in proximal tubule and thick ascending limb cells, which were further characterized by a profibrotic phenotype. Together, these data suggest that MMP-7 is a biologically plausible and promising uEV biomarker for rapid disease progression in ADPKD.
Background:
In ADPKD, there is an unmet need for early markers of rapid disease progression to facilitate counseling and selection for kidney-protective therapy. Our aim was to identify markers for rapid disease progression in uEVs.
Methods:
Six paired case-control groups ( n =10-59/group) of cases with rapid disease progression and controls with stable disease were formed from two independent ADPKD cohorts, with matching by age, sex, total kidney volume, and genetic variant. Candidate uEV biomarkers were identified by mass spectrometry and further analyzed using immunoblotting and an ELISA. Single-nucleus RNA sequencing of healthy and ADPKD tissue was used to identify the cellular origin of the uEV biomarker.
Results:
In the discovery proteomics experiments, the protein abundance of MMP-7 was significantly higher in uEVs of patients with rapid disease progression compared with stable disease. In the validation groups, a significant >2-fold increase in uEV-MMP-7 in patients with rapid disease progression was confirmed using immunoblotting. By contrast, no significant difference in MMP-7 was found in whole urine using ELISA. Compared with healthy kidney tissue, ADPKD tissue had significantly higher MMP-7 expression in proximal tubule and thick ascending limb cells with a profibrotic phenotype.
Conclusions:
Among patients with ADPKD, rapid disease progressors have higher uEV-associated MMP-7. Our findings also suggest that MMP-7 is a biologically plausible biomarker for more rapid disease progression.
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