Transcriptional regulation of the claudin-16 gene by Mg2+ availability.
OBJECTIVE
Renal tubular Mg(2+) reabsorption is mediated predominantly by the tight junction channel protein claudin-16 which is encoded by the gene CLDN16. Hypermagnesemia decreases, whereas hypomagnesemia increases Mg(2+) reabsorption. This study examines the role of claudin-16 in the adaptive response of the kidney to Mg(2+) availability.


RESULTS
Mice received a low-, normal- or high Mg(2+) diet for up to 3 days. Mg(2+)-loaded animals displayed hypermagnesemia with increasing urine Mg(2+)/Ca(2+) levels paralleled by a decrease in claudin-16 protein and mRNA in the kidney. Mg(2+)- deprived animals developed hypomagnesemia with decreasing urine Mg(2+)/Ca(2+) levels associated with an increase in claudin-16 protein and mRNA abundance. Mg(2+) depletion markedly increased and Mg(2+) load decreased endogenous claudin-16 mRNA levels in calcium-sensing receptor-transfected HEK293 cells compared with native HEK293 cells. The effect of Mg(2+) availability on the human CLDN16 (hCLDN16) gene promoter was examined. Using a 2.5kb hCLDN16 5'-flanking DNA sequence, we show that magnesium depletion increases and Mg(2+) load decreases hCLDN16 promoter activity in transfected HEK293 cells.


CONCLUSIONS
Changes in Mg(2+) availability may influence claudin-16 mediated Mg(2+) transport at the transcriptional level. The possible involvement of the cell membrane bound Ca(2+)/Mg(2+) sensing receptor or the potential role of a hypothetical Mg(2+) response element on the CLDN16 promoter in the Mg(2+)-induced response remains to be explored.
Laboratory of Developmental Nephrology, Department of Physiology and Biophysics, Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.
Edna
E
Efrati
Ayal
A
Hirsch
Orly
O
Kladnitsky
Julia
J
Rozenfeld
Marielle
M
Kaplan
Oren
O
Zinder
Israel
I
Zelikovic
D000818:Animals; D002460:Cell Line; D057167:Claudins; D004032:Diet; D005786:Gene Expression Regulation; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008274:Magnesium / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008903:Minerals / Q000097:blood / Q000652:urine; D014158:Transcription, Genetic; D014162:Transfection
D057167:Claudins; D008565:Membrane Proteins; D008903:Minerals; C502010:claudin 16; D008274:Magnesium