Role of biophysics and mechanobiology in podocyte physiology.

Podocytes form the backbone of the glomerular filtration barrier and are exposed to various mechanical forces throughout the lifetime of an individual. The highly dynamic biomechanical environment of the glomerular capillaries greatly influences the cell biology of podocytes and their pathophysiology. Throughout the past two decades, a holistic picture of podocyte cell biology has emerged, highlighting mechanobiological signalling pathways, cytoskeletal dynamics and cellular adhesion as key determinants of biomechanical resilience in podocytes. This biomechanical resilience is essential for the physiological function of podocytes, including the formation and maintenance of the glomerular filtration barrier. Podocytes integrate diverse biomechanical stimuli from their environment and adapt their biophysical properties accordingly. However, perturbations in biomechanical cues or the underlying podocyte mechanobiology can lead to glomerular dysfunction with severe clinical consequences, including proteinuria and glomerulosclerosis. As our mechanistic understanding of podocyte mechanobiology and its role in the pathogenesis of glomerular disease increases, new targets for podocyte-specific therapeutics will emerge. Treating glomerular diseases by targeting podocyte mechanobiology might improve therapeutic precision and efficacy, with potential to reduce the burden of chronic kidney disease on individuals and health-care systems alike. In this Review, the authors examine the biophysical and biomechanical properties that influence podocyte physiology as they integrate and adapt to stimuli from their dynamic environment within the glomerular capillaries. The authors also discuss how dysregulation and loss of biomechanical resilience in podocytes can contribute to kidney disease. Key points: Podocytes are crucial for maintaining glomerular filtration and must have enough biophysical resilience to adapt to (or balance) mechanical forces in their environment. Loss of biophysical resilience and aberrant mechanobiological signalling is a key feature of the pathophysiology of podocytopathies. Podocytes maintain their biophysical resilience through a complex cytoskeletal signalling network comprising force-sensitive proteins and pathways. Next-generation in vitro models that incorporate organoids, mechanical stimulation and biomimetic substrates offer promising avenues for interrogating podocyte mechanobiology. [ABSTRACT FROM AUTHOR]