Uromodulin upregulates TRPV5 by impairing caveolin-mediated endocytosis

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Abstract

Uromodulin (UMOD) is synthesized in the thick ascending limb and secreted into urine as the most abundant protein. Association studies in humans suggest protective effects of UMOD against calcium-containing kidney stones. Mice carrying mutations of Umod found in human UMOD-associated kidney disease (UAKD) and Umod-deficient mice exhibit hypercalciuria. The mechanism for UMOD regulation of urinary Ca 2+ excretion is incompletely understood. We examined if UMOD regulates TRPV5 and TRPV6, channels critical for renal transcellular Ca 2+ reabsorption. Coexpression with UMOD increased whole-cell TRPV5 current density in HEK293 cells. In biotinylation studies, UMOD increased TRPV5 cell-surface abundance. Extracellular application of purified UMOD upregulated TRPV5 current density within physiological relevant concentration ranges. UMOD exerted a similar effect on TRPV6. TRPV5 undergoes constitutive caveolin-mediated endocytosis. UMOD had no effect on TRPV5 in a caveolin-1-deficient cell line. Expression of recombinant caveolin-1 in these cells restored the ability of UMOD to upregulate TRPV5. Secretion of UAKD-mutant UMOD was markedly reduced and coexpression of mutant UMOD with TRPV5 failed to increase its current. Immunofluorescent studies demonstrated lower TRPV5 expression in Umod -/- mice compared with wild-type. UMOD upregulates TRPV5 by acting from extracellular and by decreasing endocytosis of TRPV5. The stimulation of Ca 2+ reabsorption via TRPV5 by UMOD may contribute to protection against kidney-stone formation.

Original languageEnglish (US)
Pages (from-to)130-137
Number of pages8
JournalKidney International
Volume84
Issue number1
DOIs
StatePublished - Jul 2013

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Uromodulin
Caveolins
Endocytosis
Up-Regulation
Caveolin 1
Kidney Calculi
Biotinylation
Hypercalciuria
HEK293 Cells

ASJC Scopus subject areas

  • Nephrology

Cite this

Uromodulin upregulates TRPV5 by impairing caveolin-mediated endocytosis. / Wolf, Matthias T F; Wu, Xue Ru; Huang, Chou Long.

In: Kidney International, Vol. 84, No. 1, 07.2013, p. 130-137.

Research output: Contribution to journalArticle

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