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Role of biophysics and mechanobiology in podocyte physiology

Nature Reviews Nephrology (2024)Cite this article

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Abstract

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.

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.

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Fig. 1: Role of podocyte morphology in glomerular biomechanics.
Fig. 2: Effects of external mechanical stresses on podocytes.
Fig. 3: Podocyte intracellular mechanical forces.
Fig. 4: Pathways influencing podocyte biomechanics.

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Acknowledgements

We would like to acknowledge Chiara Mariottini for critical reading of the manuscript before submission and NIH for funding (R25 DK124917 to EUA). J.H. was partly funded by T32 HD075735.

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Authors and Affiliations

  1. Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Jonathan Haydak & Evren U. Azeloglu

  2. Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Evren U. Azeloglu

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Both authors researched data for the article, made substantial contributions to discussions of the content and wrote, reviewed, and edited the manuscript before submission.

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Glossary

Buttress force

Reaction force exerted by podocytes countering dilation of the glomerular capillary.

Filopodia

Thin, spike-like projections found beyond the lamellipodia.

Foot process effacement

Morphological change in podocytes caused by cytoskeletal rearrangement in which the interdigitating foot processes become simplified and broadened, resulting in proteinuria.

Lamellipodia

Membrane protrusions found at the leading edge of cells.

Shear stress

Stress resulting from deformation (for example, due to fluid flow) parallel to the face of a material.

Stress fibres

Actomyosin bundles that serve as the primary source of contractile force in non-muscle cells.

Tensile stress

Stress resulting from a force that is stretching or elongating a material.

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Haydak, J., Azeloglu, E.U. Role of biophysics and mechanobiology in podocyte physiology. Nat Rev Nephrol (2024). https://doi.org/10.1038/s41581-024-00815-3

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