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  • Review Article
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The role of claudins in homeostasis

Nature Reviews Nephrology volume 19, pages 587–603 (2023)Cite this article

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Abstract

Sequential expression of claudins, a family of tight junction proteins, along the nephron mirrors the sequential expression of ion channels and transporters. Only by the interplay of transcellular and paracellular transport can the kidney efficiently maintain electrolyte and water homeostasis in an organism. Although channel and transporter defects have long been known to perturb homeostasis, the contribution of individual tight junction proteins has been less clear. Over the past two decades, the regulation and dysregulation of claudins have been intensively studied in the gastrointestinal tract. Claudin expression patterns have, for instance, been found to be affected in infection and inflammation, or in cancer. In the kidney, a deeper understanding of the causes as well as the effects of claudin expression alterations is only just emerging. Little is known about hormonal control of the paracellular pathway along the nephron, effects of cytokines on renal claudin expression or relevance of changes in paracellular permeability to the outcome in any of the major kidney diseases. By summarizing current findings on the role of specific claudins in maintaining electrolyte and water homeostasis, this Review aims to stimulate investigations on claudins as prognostic markers or as druggable targets in kidney disease.

Key points

  • Claudins are a family of transmembane proteins that assemble into tight junction strands and thus restrict the paracellular pathway.

  • Whereas some claudins exclusively form paracellular barriers, others confer ion selectivity with or without water permeability by forming paracellular channels.

  • Each nephron segment has its own specific claudin expression pattern that complements the specific set of transcellular channels and transporters.

  • Mutations in several claudins (claudin-2, claudin-10, claudin-16 and claudin-19) cause human hereditary diseases that affect kidney function and compromise calcium homeostasis. Common genetic variants in the claudin-2 and claudin-14 genes are risk factors for nephrolithiasis.

  • Factors (such as hormones or cytokines) and processes (transcriptional, post-translational) that regulate renal claudin expression, as well as the role of claudin dysregulation in kidney disease, are only just emerging.

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Fig. 1: Claudin structure and tight junction strand formation.
Fig. 2: Claudin distribution along the nephron.
Fig. 3: Properties of renal claudins.
Fig. 4: Major paracellular pathways for divalent cation reabsorption.
Fig. 5: Hormonal regulation of paracellular Na+ reabsorption.
Fig. 6: Number of SNPs per claudin by water, mineral and electrolyte balance category.

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Acknowledgements

The authors thank J. Piontek for providing Fig. 1a image and M. Fromm and M. A. Knepper for valuable discussion. The work of the authors is funded by the Deutsche Forschungsgemeinschaft (grant ID 318374368).

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    Luca Meoli & Dorothee Günzel

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Related links

Kidney Cell Explorer: https://cello.shinyapps.io/kidneycellexplorer/

Kidney Interactive Transcriptomics: https://humphreyslab.com/SingleCell/

Kidney Tubules Expression Atlas: https://esbl.nhlbi.nih.gov/KTEA/

Mouse Renal Epithelial Cell Atlas: https://esbl.nhlbi.nih.gov/MRECA/Nephron/

Nephroseq: https://www.nephroseq.org/resource/login.html

OMIM: https://omim.org

RNA-seq Analysis of Microdissected Rat Kidney Tubule Segments: https://esbl.nhlbi.nih.gov/helixweb/Database/NephronRNAseq/All_transcripts.html

REC dehydration database: https://endotheliomics.shinyapps.io/rec_dehydration/

Single-cell transcriptomics: https://shiny.mdc-berlin.de/humAKI/

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Meoli, L., Günzel, D. The role of claudins in homeostasis. Nat Rev Nephrol 19, 587–603 (2023). https://doi.org/10.1038/s41581-023-00731-y

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