Abstract: FR-PO222
Divergent Changes in Kidney Extracellular Matrix Stiffness in Different Mouse Models of Diabetic Nephropathy
Session Information
- Diabetic Kidney Disease: Basic - II
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Bioengineering
- 300 Bioengineering
Authors
- Sant, Snehal, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Ferrell, Nicholas J., Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background
The mechanical properties of the extracellular matrix (ECM) are important in regulating cell and tissue function, and changes in ECM stiffness contribute to a number of pathological conditions. Diabetes is characterized by dramatic changes in the structure of the kidney ECM. Glomerular and tubular basement membrane thickening and expansion of the mesangial matrix are hallmarks of diabetic nephropathy. It is not clear how structural alterations in the ECM translate into changes in the biophysical properties of the ECM in diabetic kidney disease. The goal of this work was to evaluate the stiffness of tubular basement membranes and glomerular ECM in multiple models of diabetic nephropathy of varying severity.
Methods
Tubules and glomeruli were isolated from db/db and eNOS-/- db/db mice. Tubules were subjected to tensile testing using a custom mechanical characterization method. Stress-strain response for tubular basement membrane was evaluated by measuring the force required to stretch the tubules a given length. Hyperelastic materials theory was used to model the tubular stress-strain response. Glomeruli were decellularized and subjected to compression testing to evaluate the compressive modulus of the glomerular ECM. A high deformation Hertzian contact model was used to determine glomerular stiffness.
Results
Biomechanical testing showed that tubular basement membrane stiffness was reduced in the db/db mouse at 16 weeks of age. At this time point, there was no evidence of tubulointerstitial fibrosis, but there were initial signs of renal functional declines based on increased urine albumin to creatinine ratio. In the eNOS-/- db/db mice, there was histologically evident glomerular sclerosis at 18 weeks of age. Glomerular ECM stiffness was significantly increased in a subset of glomeruli from these mice. The amount of stiffness may be related to the degree of glomerular fibrosis.
Conclusion
These data suggest that there are divergent changes in the stiffness of the kidney ECM in different animal models of diabetic nephropathy. These differences may be related to differences in the severity and/or progression of the disease in these different models. The pathophysiological consequences of these progression dependent changes in ECM stiffness will be the focus of future investigation.
Funding
- NIDDK Support