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Stressed podocytes—mechanical forces, sensors, signaling and response

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Abstract

Increased glomerular capillary pressure (glomerular hypertension) and increased glomerular filtration rate (glomerular hyperfiltration) have been proven to cause glomerulosclerosis in animal models and are likely to be operative in patients. Since podocytes cover the glomerular basement membrane, they are exposed to tensile stress due to circumferential wall tension and to fluid shear stress arising from filtrate flow through the narrow filtration slits and through Bowman’s space. In vitro evidence documents that podocytes respond to tensile stress as well as to fluid shear stress. Several proteins are discussed in this review that are expressed in podocytes and could act as mechanosensors converting mechanical force via a conformational change into a biochemical signal. The cation channels P2X4 and TRPC6 were shown to be involved in mechanosignaling in podocytes. P2X4 is activated by stretch-induced ATP release, while TRPC6 might be inherently mechanosensitive. Membrane, slit diaphragm and cell-matrix contact proteins are connected to the sublemmal actin network in podocytes via various linker proteins. Therefore, actin-associated proteins, like the proven mechanosensor filamin, are ideal candidates to sense forces in the podocyte cytoskeleton. Furthermore, podocytes express talin, p130Cas, and fibronectin that are known to undergo a conformational change in response to mechanical force exposing cryptic binding sites. Downstream of mechanosensors, experimental evidence suggests the involvement of MAP kinases, Ca2+ and COX2 in mechanosignaling and an emerging role of YAP/TAZ. In summary, our understanding of mechanotransduction in podocytes is still sketchy, but future progress holds promise to identify targets to alleviate conditions of increased mechanical load.

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Acknowledgements

The continuous support of the authors’ work by grants of the German Federal Ministry of Education and Research (BMBF), the German Research Foundation (DFG), and the European Union (EU) is gratefully acknowledged.

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  1. Department of Anatomy and Cell Biology, University Medicine Greifswald, 17489, Greifswald, Germany

    Karlhans Endlich, Felix Kliewe & Nicole Endlich

  2. Institut für Anatomie and Zellbiologie, Universitätsmedizin Greifswald, Friedrich-Loeffler-Str. 23c, 17489, Greifswald, Germany

    Karlhans Endlich

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Correspondence to Karlhans Endlich.

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This article is part of the special issue on Functional Anatomy of the Kidney in Health and Disease in Pflügers Archiv—European Journal of Physiology.

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Endlich, K., Kliewe, F. & Endlich, N. Stressed podocytes—mechanical forces, sensors, signaling and response. Pflugers Arch - Eur J Physiol 469, 937–949 (2017). https://doi.org/10.1007/s00424-017-2025-8

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