Abstract: PO1657
Podocytes Soften in Proteinuric CKD: A Potential New Mechanism for Proteinuria?
Session Information
- Podocyte Injury in Human Disease: Pathomechanism, Diagnosis, and Therapy
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1204 Podocyte Biology
Authors
- Ulloa severino, Luisa, St Michael's Hospital, Toronto, Ontario, Canada
- He, Xiaolin, St Michael's Hospital, Toronto, Ontario, Canada
- Lausecker, Franziska, The University of Manchester Faculty of Biology Medicine and Health, Manchester, Manchester, United Kingdom
- Lennon, Rachel, The University of Manchester Faculty of Biology Medicine and Health, Manchester, Manchester, United Kingdom
- Krendel, Mira, State University of New York Upstate Medical University, Syracuse, New York, United States
- Yuen, Darren A., St Michael's Hospital, Toronto, Ontario, Canada
Group or Team Name
- Yuen Lab
Background
Proteinuria is one of the most common manifestations of glomerular injury, and an important predictor of disease progression. Podocytes are a critical component of the glomerular filtration barrier, and as such podocyte injury is a major cause of proteinuria. Historically, investigators have focused on biochemical changes in podocytes that occur following podocyte injury. In contrast, little is known about the changes in the biophysical properties of these highly specialized epithelial cells.
Methods
3 different models of proteinuric glomerular disease were studied: (1) Akita+/- Ren+/- mice (a murine model of diabetes and renin-mediated hypertension that we have recently shown develops progressive glomerulosclerosis that mimics human diabetic kidney disease, n = 7), (2) Myo1e-/- mice (a mouse model of genetic FSGS characterized by deficiency of a non-muscle myosin involved in actomyosin contraction, n = 6), and (3) Col4a5-/- mice, a mouse model of Alport’s syndrome (n = 12). The stiffness of glomeruli, glomerular basement membrane (GBM), and podocytes was measured using atomic force microscopy (AFM) and associated histology (picrosirius red, silver, and WT1 staining). Similar stiffness measurements were performed in human FSGS and healthy kidney donor biopsies.
Results
AFM measurements revealed that glomerular stiffness increased in Akita+/- Ren+/- and Col4a5-/- mice, a finding that correlated with the degree of glomerulosclerosis. Glomerular stiffness was not increased in Myo1e-/- mice. GBM stiffness was increased in Akita+/- Ren+/- and Myo1e-/- mice, but not in Col4a5-/- Alport’s mice. In all 3 mouse models, as well as in human FSGS biopsies, podocytes were softer than in healthy control kidneys.
Conclusion
Taken together, these are the first data demonstrating that podocytes soften in proteinuric glomerular disease. Given the major rearrangements in the actomyosin network that occur in podocytes of proteinuric kidneys, our data suggest that podocyte softening may be a common manifestation of podocyte injury. Further work is ongoing to understand whether this softening is solely a consequence of podocyte injury, or if it also contributes to ongoing podocyte damage.