title: Claudin-16 and claudin-19 interaction is required for their assembly into tight junctions and for renal reabsorption of magnesium.
abstract: Claudins are tight junction integral membrane proteins that are key regulators of the paracellular pathway. Defects in claudin-16 (CLDN16) and CLDN19 function result in the inherited human renal disorder familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). Previous studies showed that siRNA knockdown of CLDN16 in mice results in a mouse model for FHHNC. Here, we show that CLDN19-siRNA mice also developed the FHHNC symptoms of chronic renal wasting of magnesium and calcium together with defective renal salt handling. siRNA knockdown of CLDN19 caused a loss of CLDN16 from tight junctions in the thick ascending limb (TAL) without a decrease in CLDN16 expression level, whereas siRNA knockdown of CLDN16 produced a similar effect on CLDN19. In both mouse lines, CLDN10, CLDN18, occludin, and ZO-1, normal constituents of TAL tight junctions, remained correctly localized. CLDN16- and CLDN19-depleted tight junctions had normal barrier function but defective ion selectivity. These data, together with yeast two-hybrid binding studies, indicate that a heteromeric CLDN16 and CLDN19 interaction was required for assembling them into the tight junction structure and generating cation-selective paracellular channels.
authors.affiliation: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA. jhou@dom.wustl.edu
authors.forename: Jianghui
authors.initials: J
authors.lastname: Hou
authors.forename: Aparna
authors.initials: A
authors.lastname: Renigunta
authors.forename: Antonio S
authors.initials: AS
authors.lastname: Gomes
authors.forename: Mingli
authors.initials: M
authors.lastname: Hou
authors.forename: David L
authors.initials: DL
authors.lastname: Paul
authors.forename: Siegfried
authors.initials: S
authors.lastname: Waldegger
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Goodenough
mesh_terms: D000042:Absorption; D000818:Animals; D057167:Claudins; D003001:Cloning, Molecular; D015151:Immunoblotting; D016086:Lentivirus; D008138:Loop of Henle / Q000378:metabolism*; D008274:Magnesium / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009841:Oligonucleotides / Q000235:genetics; D019108:Tight Junctions / Q000378:metabolism*
chemical_list: D057167:Claudins; C502666:Cldn19 protein, mouse; D008565:Membrane Proteins; D009841:Oligonucleotides; C502010:claudin 16; D008274:Magnesium
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