Uromodulin is expressed in the distal convoluted tubule, where it is critical for regulation of the sodium chloride cotransporter NCC

Natsuko Tokonami, Tomoaki Takata, Jan Beyeler, Iris Ehrbar, Ayumi Yoshifuji, Erik I. Christensen, Johannes Loffing, Olivier Devuyst, Eric G. Olinger

Research output: Contribution to journalArticlepeer-review

78 Citations (Scopus)

Abstract

Uromodulin, the most abundant protein in normal urine, is essentially produced by the cells lining the thick ascending limb. There it regulates the activity of the cotransporter NKCC2 and is involved in sodium chloride handling and blood pressure regulation. Conflicting reports suggested that uromodulin may also be expressed in the distal convoluted tubule (DCT) where its role remains unknown. Using microdissection studies combined with fluorescent in situ hybridization and co-immunostaining analyses, we found a significant expression of uromodulin in mouse and human DCT at approximately 10% of thick ascending limb expression levels, but restricted to the early part of the DCT (DCT1). Genetic deletion of Umod in mouse was reflected by a major shift in NCC activity from the DCT1 to the downstream DCT2 segment, paralleled by a compensatory expansion of DCT2. By increasing the distal sodium chloride and calcium ion load with chronic furosemide administration, an intrinsic compensatory defect in the DCT from Umod -/- compared to wild type mice was found manifested as sodium wasting and hypercalciuria. In line, co-expression studies in HEK cells suggested a facilitating role for uromodulin in NCC phosphorylation, possibly via SPAK-OSR1 modulation. These experiments demonstrate a significant expression of uromodulin in the early part of mouse and human DCT. Thus, biosynthesis of uromodulin in the DCT1 is critical for its function, structure and plasticity, suggesting novel links between uromodulin, blood pressure control and risk of kidney stones.

Original languageEnglish
Pages (from-to)701-715
Number of pages15
JournalKidney international
Volume94
Issue number4
DOIs
Publication statusPublished - 2018 Oct
Externally publishedYes

Keywords

  • blood pressure regulation
  • distal convoluted tubule
  • Na /Cl -cotransporter
  • salt handling
  • uromodulin

ASJC Scopus subject areas

  • Nephrology

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