Document Type

Article

Publication Date

8-23-2019

Keywords

JMG

JAX Source

Sci Rep 2019 Aug 23; 9(1):12287

Volume

9

Issue

1

First Page

12287

Last Page

12287

ISSN

2045-2322

PMID

31444371

DOI

https://doi.org/10.1038/s41598-019-48300-3

Grant

HL095668,OD020351,CA034196,American Recovery and Reinvestment Act

Abstract

Uromodulin is a zona pellucida-type protein essentially produced in the thick ascending limb (TAL) of the mammalian kidney. It is the most abundant protein in normal urine. Defective uromodulin processing is associated with various kidney disorders. The luminal release and subsequent polymerization of uromodulin depend on its cleavage mediated by the serine protease hepsin. The biological relevance of a proper cleavage of uromodulin remains unknown. Here we combined in vivo testing on hepsin-deficient mice, ex vivo analyses on isolated tubules and in vitro studies on TAL cells to demonstrate that hepsin influence on uromodulin processing is an important modulator of salt transport via the sodium cotransporter NKCC2 in the TAL. At baseline, hepsin-deficient mice accumulate uromodulin, along with hyperactivated NKCC2, resulting in a positive sodium balance and a better adaptation to water deprivation. In conditions of high salt intake, defective uromodulin processing predisposes hepsin-deficient mice to a salt-wasting phenotype, with a decreased salt sensitivity. These modifications are associated with intracellular accumulation of uromodulin, endoplasmic reticulum-stress and signs of tubular damage. These studies expand the physiological role of hepsin and uromodulin and highlight the importance of hepsin-mediated processing of uromodulin for kidney tubule homeostasis and salt sensitivity.

Comments

We thank Prof. Jan Loffing (University of Zurich) and Prof. Biff Forbush (Yale Medical School) for material, Nadine Nägele, Kanika Jain, Samyuktha Pillai, Claudia Meyer, Agnieszka Wengi and Holly Savage for expert technical assistance.

This open access article is licensed under a Creative Commons Attribution 4.0 International License

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