Abstract: FR-PO945
Targetable Biomarker in Glomerular Disease: Determining the Role of Plasminogen in Podocyte Injury
Session Information
- Glomerular Diseases: Podocyte Biology - II
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1204 Podocyte Biology
Authors
- Egerman, Marc, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Wong, Jenny, Mount Sinai School of Medicine, New York, New York, United States
- Coca, Steven G., Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Azeloglu, Evren U., Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Campbell, Kirk N., Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Raij, Leopoldo, University of Miami Miller School of Medicine, Miami, Florida, United States
Background
Recent studies have shown significant quantities of plasminogen/plasmin, or plasmin(ogen)uria, in the urine of proteinuric patients and that exposure of cultured podocytes to plasminogen can result in injury via up-regulation of endothelin-1 (ET1) and oxidative stress pathways. However, a causative role for plasminogen as a “second hit” in disease progression has yet to be demonstrated in vivo, and the associations between plasmin(ogen)uria and kidney function in glomerular diseases remains unclear.
Methods
We performed comparative studies in a puromycin aminonucleoside (PAN) nephropathy rat model treated with amiloride, which has off-target effects inhibiting plasminogen activation, and measured changes in plasmin(ogen)uria and urinary ET1 by ELISA. Western blotting, proteomics, and IF were conducted to investigate changes in ET1 and plasmin(ogen) in isolated glomeruli as well as markers of oxidative stress and podocyte homeostasis. We used a biorepository at Mount Sinai hospital to identify patients with glomerular diseases (n=128). Urine samples were measured for time-of-biopsy albuminuria and plasmin(ogen)uria to assess for correlations with kidney function outcomes by logistic and linear regression.
Results
Plasmin(ogen) was found—for the first time to our knowledge—to be strongly bound within glomeruli in PAN rats, which was later confirmed in FSGS patients. PAN-treatment was associated with increases in plasmin(ogen)uria and urinary ET1, which was rescued by amiloride. Similarly, amiloride was protective against PAN-induced glomerular injury and oxidative stress. In the patient cohort, associations were shown between plasmin(ogen)uria and edema status as well as with eGFR, independent of age and gender.
Conclusion
Here, we (i) present strong supportive evidence for a causative role of the plasmin(ogen)-system in podocyte injury, with amiloride having reno-protective properties in vivo, and (ii) advance clinical correlations of plasmin(ogen)uria as a biomarker of glomerular injury in proteinuric patients. Plasmin(ogen) may thus aggravate renal disease through direct injury to podocytes during its trans-glomerular passage in the setting of proteinuria. Given such a function, plasmin(ogen) represents an attractive target for the development of mechanistically-based novel therapeutic interventions.