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Urea transporter proteins as targets for small-molecule diuretics

  • Review Article
  • Published:

From Nature Reviews Nephrology

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Key Points

  • Urea transporter (UT) proteins facilitate the passive transport of urea driven by a concentration gradient across the cell plasma membrane in some kidney and extrarenal cells

  • The kidney expresses UT-A1 and UT-A3 in inner medullary collecting duct epithelium, UT-A2 in thin descending limbs of the loop of Henle, and UT-B in descending vasa recta endothelium

  • Kidney UTs are required for the generation of concentrated urine

  • High-throughput screening has identified potent and selective small-molecule inhibitors of UT-A and UT-B that produce a salt-sparing diuresis in rodent models

  • UT inhibitors may be useful alone or in combination with conventional diuretics for therapy of various oedemas and hyponatraemias

Abstract

Conventional diuretics such as furosemide and thiazides target salt transporters in kidney tubules, but urea transporters (UTs) have emerged as alternative targets. UTs are a family of transmembrane channels expressed in a variety of mammalian tissues, in particular the kidney. UT knockout mice and humans with UT mutations exhibit reduced maximal urinary osmolality, demonstrating that UTs are necessary for the concentration of urine. Small-molecule screening has identified potent and selective inhibitors of UT-A, the UT protein expressed in renal tubule epithelial cells, and UT-B, the UT protein expressed in vasa recta endothelial cells. Data from UT knockout mice and from rodents administered UT inhibitors support the diuretic action of UT inhibition. The kidney-specific expression of UT-A1, together with high selectivity of the small-molecule inhibitors, means that off-target effects of such small-molecule drugs should be minimal. This Review summarizes the structure, expression and function of UTs, and looks at the evidence supporting the validity of UTs as targets for the development of salt-sparing diuretics with a unique mechanism of action. UT-targeted inhibitors may be useful alone or in combination with conventional diuretics for therapy of various oedemas and hyponatraemias, potentially including those refractory to treatment with current diuretics.

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Figure 1: Schematic representation of the primary structures of mammalian UT-A isoforms.
Figure 2: Molecular structure of bovine UT-B.
Figure 3: Expression of the major mammalian UT isoforms in the kidney.
Figure 4: Assays of UT-mediated urea transport.
Figure 5: UTBinh-14 inhibition of UT-B.
Figure 6: Small-molecule inhibitors of UT-A.
Figure 7: UT inhibitor diuretic action in rodents.

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Acknowledgements

M.O.A. and A.S.V. are funded by the National Institutes of Health, and A.S.V. is also funded by the Guthy–Jackson Charitable Foundation and the Cystic Fibrosis Foundation.

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Authors and Affiliations

  1. Departments of Medicine and Physiology, University of California, 513 Parnassus Avenue, San Francisco, 94143, CA, USA

    Cristina Esteva-Font & Alan S. Verkman

  2. Department of Chemistry and Biochemistry, San Francisco State University, 1600 Holloway Avenue, San Francisco, 94132, CA, USA

    Marc O. Anderson

Authors
  1. Cristina Esteva-Font
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  2. Marc O. Anderson
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  3. Alan S. Verkman
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Contributions

C.E.-F., M.O.A. and A.S.V. researched data for the article, provided substantial contributions to discussions of content, and wrote the article, and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Alan S. Verkman.

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Competing interests

C.E.-F., M.O.A. and A.S.V. declare that they are named inventors on patent applications for urea transporter screening methods and small-molecule urea transporter inhibitors. Patent rights are assigned to the authors' respective institutions, and patents have not yet been licensed.

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Esteva-Font, C., Anderson, M. & Verkman, A. Urea transporter proteins as targets for small-molecule diuretics. Nat Rev Nephrol 11, 113–123 (2015). https://doi.org/10.1038/nrneph.2014.219

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