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

  • Tokonami N Institute of Physiology, University of Zurich, Zurich, Switzerland.
  • Takata T Institute of Physiology, University of Zurich, Zurich, Switzerland.
  • Beyeler J Institute of Physiology, University of Zurich, Zurich, Switzerland.
  • Ehrbar I Institute of Physiology, University of Zurich, Zurich, Switzerland.
  • Yoshifuji A Institute of Physiology, University of Zurich, Zurich, Switzerland.
  • Christensen EI Department of Biomedicine, Aarhus University, Aarhus, Denmark.
  • Loffing J Institute of Anatomy, University of Zurich, Zurich, Switzerland.
  • Devuyst O Institute of Physiology, University of Zurich, Zurich, Switzerland. Electronic address: olivier.devuyst@uzh.ch.
  • Olinger EG Institute of Physiology, University of Zurich, Zurich, Switzerland.
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  • 2018-07-16
Published in:
  • Kidney international. - 2018
Na(+)/Cl(−)-cotransporter
blood pressure regulation
distal convoluted tubule
salt handling
uromodulin
Animals
Furosemide
Gene Expression
HEK293 Cells
Humans
Hypercalciuria
Kidney Tubules, Distal
Male
Mice
Mice, Knockout
Phosphorylation
RNA, Messenger
Sodium
Sodium Potassium Chloride Symporter Inhibitors
Solute Carrier Family 12, Member 1
Uromodulin
English 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.
Language
  • English
Open access status
hybrid
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Persistent URL
https://folia.unifr.ch/global/documents/48394
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