Phosphorylated claudin-16 interacts with Trpv5 and regulates transcellular calcium transport in the kidney

Jianghui Hou, Vijay Renigunta, Mingzhu Nie, Abby Sunq, Nina Himmerkus, Catarina Quintanova, Markus Bleich, Aparna Renigunta, Matthias Tilmann Florian Wolf

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) was previously considered to be a paracellular channelopathy caused by mutations in the claudin-16 and claudin-19 genes. Here, we provide evidence that a missense FHHNC mutation c.908C>G (p.T303R) in the claudin-16 gene interferes with the phosphorylation in the claudin-16 protein. The claudin-16 protein carrying phosphorylation at residue T303 is localized in the distal convoluted tubule (DCT) but not in the thick ascending limb (TAL) of the mouse kidney. The phosphomimetic claudin-16 protein carrying the T303E mutation but not the wildtype claudin-16 or the T303R mutant protein increases the Trpv5 channel conductance and membrane abundance in human kidney cells. Phosphorylated claudin-16 and Trpv5 are colocalized in the luminal membrane of the mouse DCT tubule; phosphomimetic claudin-16 and Trpv5 interact in the yeast and mammalian cell membranes. Knockdown of claudin-16 gene expression in transgenic mouse kidney delocalizes Trpv5 from the luminal membrane in the DCT. Unlike wildtype claudin-16, phosphomimetic claudin-16 is delocalized from the tight junction but relocated to the apical membrane in renal epithelial cells because of diminished binding affinity to ZO-1. High-Ca2+ diet reduces the phosphorylation of claudin-16 protein at T303 in the DCT of mouse kidney via the PTH signaling cascade. Knockout of the PTH receptor, PTH1R, from the mouse kidney abrogates the claudin-16 phosphorylation at T303. Together, these results suggest a pathogenic mechanism for FHHNC involving transcellular Ca2+ pathway in the DCT and identify a molecular component in renal Ca2+ homeostasis under direct regulation of PTH.

Original languageEnglish (US)
Pages (from-to)19176-19186
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number38
DOIs
StatePublished - Sep 17 2019

Keywords

  • Calcium
  • Claudin
  • PTH
  • Tight junction
  • Trpv5

ASJC Scopus subject areas

  • General

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