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The glomerular endothelial glycocalyx as a therapeutic target in proteinuric kidney disease

Nature Reviews Nephrology volume 22, pages 229–241 (2026)Cite this article

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Abstract

Endothelial glycocalyx lines every blood vessel throughout the body, and has key roles in vascular biology, including vascular permeability and inflammation. Accumulated evidence from the past 15 years shows that the glomerular endothelial glycocalyx is a vital component of the glomerular filtration barrier, which limits the filtration of macromolecules such as albumin. However, the contribution of endothelial glycocalyx to the pathogenesis of proteinuria and its potential as a therapeutic target have not been fully explored. Experimental disruption of the glomerular endothelial glycocalyx increases glomerular albumin permeability, and loss of endothelial glycocalyx integrity has been observed in diseases that compromise the glomerular filtration barrier, including diabetic kidney disease and other glomerular diseases. Strategies to protect the endothelial glycocalyx have successfully reduced proteinuria in animal models of proteinuric kidney disease, indicating that therapeutic modification of the endothelial glycocalyx can achieve important functional benefits. Moreover, drugs with recognized roles in renal medicine (for example, mineralocorticoid receptor antagonists) reduce albuminuria at least in part by protecting the endothelial glycocalyx. Recognition of the glomerular endothelial glycocalyx as a therapeutic target could aid the development of drugs that specifically target the endothelial glycocalyx with potentially greater benefits than those that do so incidentally.

Key points

  • Under physiological conditions, in systemic and glomerular capillaries, the endothelial glycocalyx is a key component of the vessel wall that limits permeability to macromolecules.

  • Disruption of the glomerular endothelial glycocalyx increases glomerular albumin permeability and albuminuria.

  • Endothelial glycocalyx damage contributes to albuminuria in diabetic kidney disease and other glomerular diseases, including inflammatory diseases; it may represent a final common pathway of glomerular proteinuria.

  • Animal models demonstrate that the endothelial glycocalyx can be therapeutically restored, leading to important reductions in glomerular permeability and albuminuria; these changes could be clinically relevant, but require assessment in a clinical setting.

  • Some existing standard-of-care drugs have been shown to reduce proteinuria by protecting the endothelial glycocalyx; other therapeutics may do so by the same mechanism.

  • Improved understanding of the mechanisms of endothelial glycocalyx damage has the potential to aid the design of drugs that target the glomerular endothelial glycocalyx to reduce proteinuria and slow progression of glomerular disease.

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Fig. 1: The endothelial glycocalyx.
Fig. 2: The glomerular endothelial glycocalyx.
Fig. 3: Imaging techniques enable visualization of the glomerular endothelial glycocalyx in kidney tissue sections.
Fig. 4: Glomerular endothelial glycocalyx depth and albumin permeability correlate in models of diabetic kidney disease.
Fig. 5: Glomerular endothelial glycocalyx damage in diabetic kidney disease and inflammation.

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  1. Bristol Renal, Bristol Medical School, University of Bristol, Bristol, UK

    Monica Gamez, Raina D. Ramnath, Matthew J. Butler, Rebecca R. Foster & Simon C. Satchell

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  2. Raina D. Ramnath
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S.C.S. conceived the article and its structure. The authors contributed equally to all other aspects of the article.

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Gamez, M., Ramnath, R.D., Butler, M.J. et al. The glomerular endothelial glycocalyx as a therapeutic target in proteinuric kidney disease. Nat Rev Nephrol 22, 229–241 (2026). https://doi.org/10.1038/s41581-025-01028-y

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