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The roles of hyaluronan in kidney development, physiology and disease

Nature Reviews Nephrology (2024)Cite this article

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Abstract

The hyaluronan (HA) matrix in the tissue microenvironment is crucial for maintaining homeostasis by regulating inflammatory signalling, endothelial–mesenchymal transition and cell migration. During development, covalent modifications and osmotic swelling of HA create mechanical forces that initiate midgut rotation, vascular patterning and branching morphogenesis. Together with its main cell surface receptor, CD44, HA establishes a physicochemical scaffold at the cell surface that facilitates the interaction and clustering of growth factors and receptors that is required for normal physiology. High-molecular-weight HA, tumour necrosis factor-stimulated gene 6, pentraxin 3 and CD44 form a stable pericellular matrix that promotes tissue regeneration and reduces inflammation. By contrast, breakdown of high-molecular-weight HA into depolymerized fragments by hyaluronidases triggers inflammatory signalling, leukocyte migration and angiogenesis, contributing to tissue damage and fibrosis in kidney disease. Targeting HA metabolism is challenging owing to its dynamic regulation and tissue-specific functions. Nonetheless, modulating HA matrix functions by targeting its binding partners holds promise as a therapeutic strategy for restoring tissue homeostasis and mitigating pathological processes. Further research in this area is warranted to enable the development of novel therapeutic approaches for kidney and other diseases characterized by dysregulated HA metabolism.

Key points

  • Hyaluronan (HA) is a key component of the extracellular matrix that has critical roles in tissue homeostasis, organogenesis, cell signalling, cell migration and regulation of immune responses.

  • Together with its cell surface receptor CD44 and HA-binding proteins such as TSG6 and pentraxin3, high-molecular-weight (HMW)-HA creates a stable pericellular matrix that facilitates tissue regeneration and reduces inflammation.

  • Depolymerization of HMW-HA enables tissue remodelling and generates HA fragments that can activate inflammatory signalling, recruit leukocytes and promote angiogenesis.

  • During development, covalent modifications and osmotic swelling of HA create mechanical forces that initiate midgut rotation, vascular patterning and branching morphogenesis.

  • In kidney injury and disease, synthesis of HMW-HA contributes to tissue regeneration, whereas dysregulated breakdown of HA has been associated with inflammation, hyalinosis and fibrosis; in renal cell carcinoma, high tumour levels of HA are associated with an unfavourable prognosis.

  • HA metabolism is an unlikely therapeutic target owing to its dynamic, tissue-specific regulation and fundamental importance for tissue homeostasis; however, HA binding partners could potentially be targeted to modulate HA matrix functions and mitigate pathological processes in kidney disease.

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Fig. 1: Hyaluronan biosynthesis by hyaluronan synthase 2 and its catabolic pathways.
Fig. 2: Interactions of hyaluronan with the extracellular matrix.
Fig. 3: Hyaluronan determines gut laterality and vascular patterning.
Fig. 4: Hyaluronan–CD44 interactions in kidney development.

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Acknowledgements

The authors thank S. M. Chuva de Sousa Lopes for providing the fetal tissue sample used in Fig. 4; W. M. P. J. Sol for processing and immune fluorescence staining of the tissue sample, and M. Zuurmond for editing and drafting the originally submitted versions of the figures. The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW) is supported by Novo Nordisk Foundation grants (NNF21CC0073729). Some of the authors’ work was funded through the Dutch Kidney Foundation (GLYCOREN Consortium grant no. CP09.03).

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Authors and Affiliations

  1. Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands

    Ton J. Rabelink, Gangqi Wang & Bernard M. van den Berg

  2. The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, The Netherlands

    Ton J. Rabelink & Bernard M. van den Berg

  3. Children’s Hospital of Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China

    Gangqi Wang

  4. Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands

    Johan van der Vlag

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T.J.R. and B.M.v.d.B. primarily researched the data for the article and wrote the text. G.W. and J.v.d.V. contributed to discussions on the interpretation of the literature and reviewed and edited the manuscript before submission.

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Rabelink, T.J., Wang, G., van der Vlag, J. et al. The roles of hyaluronan in kidney development, physiology and disease. Nat Rev Nephrol (2024). https://doi.org/10.1038/s41581-024-00883-5

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