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Signal transduction in podocytes—spotlight on receptor tyrosine kinases

Nature Reviews Nephrology volume 10, pages 104–115 (2014)Cite this article

Subjects

Key Points

  • Podocytes respond to hormones and growth factors that are present in the circulation or locally produced in the glomerulus

  • A variety of receptors on the cell surface are thought to enable podocytes to respond to these external stimuli

  • The podocyte response to growth factors does not involve cell proliferation, but does include mitosis and hypertrophic cell growth, eventually leading to pathological alterations

  • Growth factors signal via receptor tyrosine kinases (RTKs), which are promising targets for cancer therapy

  • To understand and interfere with the pathological effects of growth factors on podocytes and the glomerular filter, their precise receptors must be identified and characterized

  • RTK inhibitors that are already used in cancer therapy might be promising new treatment options for proteinuric kidney diseases

Abstract

The mammalian kidney filtration barrier is a complex multicellular, multicomponent structure that maintains homeostasis by regulating electrolytes, acid–base balance, and blood pressure (via maintenance of salt and water balance). To perform these multiple functions, podocytes—an important component of the filtration apparatus—must process a series of intercellular signals. Integrating these signals with diverse cellular responses enables a coordinated response to various conditions. Although mature podocytes are terminally differentiated and cannot proliferate, they are able to respond to growth factors. It is possible that the initial response of podocytes to growth factors is beneficial and protective, and might include the induction of hypertrophic cell growth. However, extended and/or uncontrolled growth factor signalling might be maladaptive and could result in the induction of apoptosis and podocyte loss. Growth factors signal via the activation of receptor tyrosine kinases (RTKs) on their target cells and around a quarter of the 58 RTK family members that are encoded in the human genome have been identified in podocytes. Pharmacological inhibitors of many RTKs exist and are currently used in experimental and clinical cancer therapy. The identification of pathological RTK-mediated signal transduction pathways in podocytes could provide a starting point for the development of novel therapies for glomerular disorders.

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Figure 1: Podocytes form complex communication networks with their environment and are in constant contact with a variety of signal sources and receivers, including other glomerular cell types and the extracellular matrix.
Figure 2: Cell signalling receptors differ in their mechanisms of activation and signal transmission, subcellular localization, and ligand binding.

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Acknowledgements

J. Reiser's research is supported by NIH grants DK073495, DK089394, DK093773 and DK101350. S. Sever's research is funded by NIH grant DK087985. C. Faul's research is funded by a Carl W. Gottschalk Research Scholar Grant from the American Society of Nephrology.

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Authors and Affiliations

  1. Department of Medicine, Rush University Medical Center, 1735 West Harrison Street, Cohn Building, Suite 724, Chicago, 60612, IL, USA

    Jochen Reiser

  2. Department of Medicine, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Charlestown, 02129, MA, USA

    Sanja Sever

  3. Division of Nephrology and Hypertension, University of Miami Miller School of Medicine, 1580 North West 10th Avenue (R-762), Batchelor Building 626, Miami, 33136, FL, USA

    Christian Faul

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J. Reiser and C. Faul researched the data and wrote the article. All authors made a substantial contribution to discussions of the content and reviewed and/or edited the manuscript before submission.

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Competing interests

J. Reiser has issued and pending patents on the development of novel kidney protective therapeutics. He stands to gain royalties from their commercialization. S. Sever and C. Faul declare no competing interests.

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Reiser, J., Sever, S. & Faul, C. Signal transduction in podocytes—spotlight on receptor tyrosine kinases. Nat Rev Nephrol 10, 104–115 (2014). https://doi.org/10.1038/nrneph.2013.274

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