Date of Award
8-1-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Podocytes are specialized epithelial cells that form an essential part of the kidney’s glomerular filtration barrier (GFB). Their interdigitating foot processes create slit diaphragms that filter the blood, allowing only small (<60 kDa) molecules to enter Bowman’s space. However, podocyte injury leading to foot process effacement and detachment can disrupt this intricate structure, compromising kidney function and contributing to chronic kidney disease. This dissertation investigates the mechanical factors governing podocyte adhesion and injury through a combination of mathematical modeling, in vitro experimentation, and in vivo studies. We developed a model predicting how fluid shear stress and podocyte contractility influence integrin-mediated adhesion stability. The model suggests an optimal range of mechanical forces is needed to maintain podocyte attachment. To test these predictions, we established mouse models with altered glomerular filtration rates and pharmacologically modulated podocyte contractility. Super-resolution imaging revealed shear-dependent changes in integrin localization consistent with our model. We also identified and characterized sarcomere-like structures (SLSs) in podocytes that appear to enhance contractility and adhesion strength in injured podocytes. Using micropatterned hydrogels, we showed these SLSs to be mechanosensitive and associated with improved resistance to detachment under flow. Finally, we investigated how the protein CD2AP regulates podocyte contractility and adhesion through effects on myosin activity and the RhoA pathway. Collectively, this work provides new insights into the mechanical regulation of podocyte adhesion and injury. By elucidating key mechanical determinants of podocyte stability and mechanobiology, these findings may inform the development of future therapeutic strategies.
Language
English (en)
Chair
Guy Genin
Committee Members
Hani Suleiman