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Developmental signalling pathways in renal fibrosis: the roles of Notch, Wnt and Hedgehog

Nature Reviews Nephrology volume 12, pages 426–439 (2016)Cite this article

Subjects

Key Points

  • Kidney fibrosis, the histological manifestation of functional decline in the kidney, is a reactive process that develops in response to excessive epithelial injury and inflammation

  • In fibrosis, epithelial cells and their vascular capillary bed are lost, while activated myofibroblasts, matrix and inflammatory cells accumulate

  • Tissue injury causes activation of developmental pathways, and several reports have shown that fibrosis is associated with increased expression and activity of Notch, Wnt and Hedgehog (Hh) signalling

  • Although activation of these pathways might be important for regeneration of the damaged organ, excessive stimulation contributes to fibrosis development

  • Notch and Wnt signalling have been shown to have a role in epithelial dedifferentiation; Wnt and Hh signalling can induce myofibroblast transformation and proliferation

  • Decreasing the activity of Notch, Wnt, or Hh signalling could potentially be a new therapeutic strategy to ameliorate the development of chronic kidney disease

Abstract

Kidney fibrosis is a common histological manifestation of functional decline in the kidney. Fibrosis is a reactive process that develops in response to excessive epithelial injury and inflammation, leading to myofibroblast activation and an accumulation of extracellular matrix. Here, we describe how three key developmental signalling pathways — Notch, Wnt and Hedgehog (Hh) — are reactivated in response to kidney injury and contribute to the fibrotic response. Although transient activation of these pathways is needed for repair of injured tissue, their sustained activation is thought to promote fibrosis. Excessive Wnt and Notch expression prohibit epithelial differentiation, whereas increased Wnt and Hh expression induce fibroblast proliferation and myofibroblastic transdifferentiation. Notch, Wnt and Hh are fundamentally different signalling pathways, but their choreographed activation seems to be just as important for fibrosis as it is for embryonic kidney development. Decreasing the activity of Notch, Wnt or Hh signalling could potentially provide a new therapeutic strategy to ameliorate the development of fibrosis in chronic kidney disease.

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Figure 1: Development of kidney fibrosis.
Figure 2: Notch signalling in renal fibrosis.
Figure 3: Dysregulation of Wnt signalling leads to the development of renal fibrosis.
Figure 4: Hedgehog (Hh) signalling and renal fibrosis.

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Acknowledgements

This work was supported by the NIH grants R01 DK076077 and DK087635 to K.S. and by grants of the Innovative Medizinische Forschung and Dr. Werner Jackstädt-Stiftung to M.E. and H.P. We apologize to all colleagues whose important findings could not be cited owing to space limitations.

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  1. Renal Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, 415 Curie Boulevard, 415 Clinical Research Building, Philadelphia, 19104, Pennsylvania, USA

    Maria Edeling, Grace Ragi, Shizheng Huang & Katalin Susztak

  2. Department of Molecular Nephrology, Internal Medicine D, University Hospital, Albert-Schweitzer-Straße 33, Münster, 48149, Germany

    Maria Edeling & Hermann Pavenstädt

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  1. Maria Edeling
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Contributions

M.E., S.H. and G.R. researched data for the article. M.E. and K.S. discussed the article's content, after which M.E., S.H., G.R. and K.S. wrote the manuscript. H.P. reviewed the manuscript before submission.

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Correspondence to Katalin Susztak.

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Competing interests

M.E. has been employed by Boehringer Ingelheim since January 2016. The Susztak laboratory has received research support from Boehringer Ingelheim, Biogen and Eli Lilly & Company.

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Edeling, M., Ragi, G., Huang, S. et al. Developmental signalling pathways in renal fibrosis: the roles of Notch, Wnt and Hedgehog. Nat Rev Nephrol 12, 426–439 (2016). https://doi.org/10.1038/nrneph.2016.54

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