Targeted deletion of murine Cldn16 identifies extra- and intrarenal compensatory mechanisms of Ca2+ and Mg2+ wasting.
Claudin-16 (CLDN16) is critical for renal paracellular epithelial transport of Ca(2+) and Mg(2+) in the thick ascending loop of Henle. To gain novel insights into the role of CLDN16 in renal Ca(2+) and Mg(2+) homeostasis and the pathological mechanisms underlying a human disease associated with CLDN16 dysfunction [familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), OMIM 248250], we generated a mouse model of CLDN16 deficiency. Similar to patients, CLDN16-deficient mice displayed hypercalciuria and hypomagnesemia. Contrary to FHHNC patients, nephrocalcinosis was absent in our model, indicating the existence of compensatory pathways in ion handling in this model. In line with the renal loss of Ca(2+), compensatory mechanisms like parathyroid hormone and 1,25(OH)(2)D(3) were significantly elevated. Also, gene expression profiling revealed transcriptional upregulation of several Ca(2+) and Mg(2+) transport systems including Trpv5, Trpm6, and calbindin-D9k. Induced gene expression was also seen for the transcripts of two putative Mg(2+) transport proteins, Cnnm2 and Atp13a4. Moreover, urinary pH was significantly lower when compared with wild-type mice. Taken together, our findings demonstrate that loss of CLDN16 activity leads to specific alterations in Ca(2+) and Mg(2+) homeostasis and that CLDN16-deficient mice represent a useful model to further elucidate pathways involved in renal Ca(2+) and Mg(2+) handling.
Dept. of Pediatric Nephrology, Charité, CVK, Augustenburger Platz 1, 13353 Berlin, Germany.
Constanze
C
Will
Tilman
T
Breiderhoff
Julia
J
Thumfart
Marchel
M
Stuiver
Kathrin
K
Kopplin
Kerstin
K
Sommer
Dorothee
D
Günzel
Uwe
U
Querfeld
Iwan C
IC
Meij
Qixian
Q
Shan
Markus
M
Bleich
Thomas E
TE
Willnow
Dominik
D
Müller
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000378:metabolism; D057167:Claudins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D017353:Gene Deletion; D006706:Homeostasis / Q000502:physiology; D053565:Hypercalciuria / Q000378:metabolism* / Q000503:physiopathology; D008274:Magnesium / Q000378:metabolism*; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D009397:Nephrocalcinosis / Q000378:metabolism* / Q000503:physiopathology; D015499:Renal Tubular Transport, Inborn Errors / Q000378:metabolism* / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology
D027682:Cation Transport Proteins; D057167:Claudins; C510868:Cnnm2 protein, mouse; D026901:Membrane Transport Proteins; C502010:claudin 16; D000251:Adenosine Triphosphatases; C550805:ATP13A4 protein, mouse; D008274:Magnesium; D002118:Calcium