Abstract: PO1398
Increased Glomerular Parietal Epithelial Cell Expression of Cathepsins C and B in Anti-Thy1.1 Mouse Model of FSGS
Session Information
- Glomerular Diseases: Fibrosis and Extracellular Matrix
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix
Authors
- Merchant, Michael, University of Louisville School of Medicine, Louisville, Kentucky, United States
- Barati, Michelle T., University of Louisville School of Medicine, Louisville, Kentucky, United States
- McLeish, Kenneth R., University of Louisville School of Medicine, Louisville, Kentucky, United States
- Klein, Jon B., University of Louisville School of Medicine, Louisville, Kentucky, United States
- Smeets, Bart, Radboudumc, Nijmegen, Gelderland, Netherlands
Background
Focal segmental glomerulosclerosis (FSGS) is characterized by replacement of glomerular capillaries by extracellular matrix (ECM). The collapsing FSGS (cFSGS) variant exhibits a poor prognosis and response to therapy. We recently reported that activated PECs migrate into glomerular tufts in human cFSGS and demonstrate increased cathepsins C and B expression. The absence of cathepsins B and C within normal glomerular tufts suggests these proteases may represent novel mediators of PEC-mediated glomerulosclerosis leading to collapse. We addressed the hypothesis that activated PECs migrate expressing cathepsins C and B migrate into glomerular PECs in a mouse model of cFSGS
Methods
Thy1.1 transgenic mice were injected with either saline (vehicle control) or anti-Thy1.1 antibody (19XE5; 1mg/mouse) to induce FSGS. Mice were sacrificed 4, 7, and 21 days after injection. Kidney sections were subjected to immunofluorescence staining for claudin-1, a marker of PECs, and cathepsin C or cathepsin B. Images were acquired by confocal microscopy.
Results
Claudin-1, cathepsin C, and cathepsin B co-localized to glomerular parietal epithelial cells lining Bowman’s capsule in vehicle control mice. On day 4 after anti-Thy1.1 administration, claudin-1 staining showed migration of PECs into glomerular tufts in more than half of the glomeruli. Both cathepsin B and C staining co-localized to claudin-1 positive cells within glomerular tufts. PECs in the Bowman’s capsule with hypertrophied morphology, suggesting activation, demonstrated increased expression of cathepsins C and B. Claudin-1 and cathepsins B and C co-localized within glomeruli on days 7 and 21 after anti-Thy1.1 administration, however, the number of stained cells per glomerulus and the percent glomeruli with positively stained cells in the glomerular tuft appeared decreased.
Conclusion
Glomerular PECs migrate into glomerular tufts and show increased expression of cathepsins C and B in the anti-thy1.1 model of cFSGS, recapitulating our findings in human cFSGS biopsies. The Thy1.1 mouse model of cFSGS can be used to define the role of PEC expression of cathepsins B and C in the pathogenesis of human cFSGS.
Funding
- Clinical Revenue Support