PMID- 17442678
OWN - NLM
STAT- MEDLINE
DCOM- 20070710
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 282
IP  - 23
DP  - 2007 Jun 8
TI  - Transgenic RNAi depletion of claudin-16 and the renal handling of magnesium.
PG  - 17114-22
AB  - Tight junctions play a key role in mediating paracellular ion reabsorption in the 
      kidney. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) 
      is a human disorder caused by mutations in the tight junction protein claudin-16. 
      However, the molecular mechanisms underlining the renal handling of magnesium and 
      its dysfunction causing FHHNC are unknown. Here we show that claudin-16 plays a 
      key role in maintaining the paracellular cation selectivity of the thick 
      ascending limbs of the nephron. Using RNA interference, we have generated 
      claudin-16-deficient mouse models. Claudin-16 knock-down (KD) mice exhibit 
      chronic renal wasting of magnesium and calcium and develop renal 
      nephrocalcinosis. Our data suggest that claudin-16 forms a non-selective 
      paracellular cation channel, rather than a selective Mg(2+)/Ca(2+) channel as 
      previously proposed. Our study highlights the pivotal importance of the tight 
      junction in renal control of ion homeostasis and provides answer to the 
      pathogenesis of FHHNC. We anticipate our study to be a starting point for more 
      sophisticated in vivo analysis of tight junction proteins in renal functions. 
      Furthermore, tight junction proteins could be major targets of drug development 
      for electrolyte disorders.
FAU - Hou, Jianghui
AU  - Hou J
AD  - Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, 
      USA.
FAU - Shan, Qixian
AU  - Shan Q
FAU - Wang, Tong
AU  - Wang T
FAU - Gomes, Antonio S
AU  - Gomes AS
FAU - Yan, QingShang
AU  - Yan Q
FAU - Paul, David L
AU  - Paul DL
FAU - Bleich, Markus
AU  - Bleich M
FAU - Goodenough, Daniel A
AU  - Goodenough DA
LA  - eng
GR  - EY014127/EY/NEI NIH HHS/United States
GR  - GM18974/GM/NIGMS NIH HHS/United States
GR  - GM37751/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20070418
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Claudins)
RN  - 0 (DNA Primers)
RN  - 0 (Membrane Proteins)
RN  - 0 (claudin 16)
RN  - I38ZP9992A (Magnesium)
SB  - IM
MH  - Animals
MH  - Base Sequence
MH  - Claudins
MH  - DNA Primers
MH  - Kidney/*metabolism
MH  - Lentivirus/genetics
MH  - Magnesium/*metabolism
MH  - Membrane Proteins/genetics/*physiology
MH  - Mice
MH  - Mice, Knockout
MH  - Microscopy, Confocal
MH  - *RNA Interference
EDAT- 2007/04/20 09:00
MHDA- 2007/07/11 09:00
CRDT- 2007/04/20 09:00
PHST- 2007/04/20 09:00 [pubmed]
PHST- 2007/07/11 09:00 [medline]
PHST- 2007/04/20 09:00 [entrez]
AID - S0021-9258(19)57657-8 [pii]
AID - 10.1074/jbc.M700632200 [doi]
PST - ppublish
SO  - J Biol Chem. 2007 Jun 8;282(23):17114-22. doi: 10.1074/jbc.M700632200. Epub 2007 
      Apr 18.