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Protein handling in kidney tubules

Nature Reviews Nephrology volume 21, pages 241–252 (2025)Cite this article

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Abstract

The kidney proximal tubule reabsorbs and degrades filtered plasma proteins to reclaim valuable nutrients and maintain body homeostasis. Defects in this process result in proteinuria, one of the most frequently used biomarkers of kidney disease. Filtered proteins enter proximal tubules via receptor-mediated endocytosis and are processed within a highly developed apical endo-lysosomal system (ELS). Proteinuria is a strong risk factor for chronic kidney disease progression and genetic disorders of the ELS cause hereditary kidney diseases, so deepening understanding of how the proximal tubule handles proteins is crucial for translational nephrology. Moreover, the ELS is both an entry point for nephrotoxins that induce tubular damage and a target for novel therapies to prevent it. Cutting-edge research techniques, such as functional intravital imaging and computational modelling, are shedding light on spatial and integrative aspects of renal tubular protein processing in vivo, how these are altered under pathological conditions and the consequences for other tubular functions. These insights have potentially important implications for understanding the origins of systemic complications arising in proteinuric states, and might lead to the development of new ways of monitoring and treating kidney diseases.

Key points

  • Uptake and degradation of filtered plasma proteins by kidney proximal tubules (PTs) is an important process in kidney physiology and body homeostasis. Defects in protein reabsorption lead to proteinuria, one of the most widely used disease biomarkers in nephrology.

  • PT cells are highly adapted to protein uptake and processing. These cells express large, multi-ligand receptors that bind a wide range of proteins and facilitate their internalization, and have a sophisticated apical endo-lysosomal system (ELS) that rapidly sorts and metabolizes proteins.

  • Protein uptake occurs mainly in the early PT, whereas small peptides are reclaimed in later regions, which shapes the axial topography of the PT. Some studies suggest that early PT cells release endocytic material, which can then be reabsorbed downstream, suggesting that tubular protein metabolism is an integrated process.

  • In response to increased glomerular protein filtration, PTs ramp up endocytic activity and uptake extends to the later regions to limit urinary protein loss. However, this axial remodelling might result in loss of other tubular functions, and dramatic increases in protein filtration can overwhelm and damage PTs, which is likely to be an important pathogenic mechanism in proteinuric kidney diseases.

  • Genetic defects in the PT ELS cause proteinuria and progressive loss of kidney function. Elucidation of underlying disease pathways is helping to identify potential molecular targets for therapeutic intervention.

  • The ELS provides protein nephrotoxins with an entry point into PT cells; temporary blockade of endocytosis might lower toxin uptake and reduce tubular damage. Moreover, conjugating compounds to proteins or peptides provides a mechanism for targeting PTs in vivo in drug development.

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Fig. 1: Adaptations of proximal tubular cells to protein processing.
Fig. 2: Axial pattern of protein and peptide uptake along the proximal tubule.
Fig. 3: Consequences of increasing glomerular protein filtration on the proximal tubule.
Fig. 4: Axial patterns of protein uptake along the proximal tubule in disease states.

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Acknowledgements

A.M.H. has received support from the Swiss National Centre for Competence in Research (NCCR) Kidney Control of Homeostasis and the Swiss National Science Foundation.

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  1. Institute of Anatomy, University of Zurich, Zurich, Switzerland

    Andrew M. Hall

  2. Zurich Kidney Center, University of Zurich, Zurich, Switzerland

    Andrew M. Hall

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Correspondence to Andrew M. Hall.

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A.M.H. has received consultancy fees from Proteinqure and AstraZeneca.

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Hall, A.M. Protein handling in kidney tubules. Nat Rev Nephrol 21, 241–252 (2025). https://doi.org/10.1038/s41581-024-00914-1

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