Targeted deletion of murine Cldn16 identifies extra- and intrarenal compensatory mechanisms of Ca2+ and Mg2+ wasting

Will C, Breiderhoff T, Thumfart J, Stuiver M, Kopplin K, Sommer K, Gunzel D, Querfeld U, Meij IC, Shan Q, Bleich M, Willnow TE, Muller D. Targeted deletion of murine Cldn16 identifies extra-and intrarenal compensatory mechanisms of Ca2+ and Mg2+ wasting. Am J Physiol Renal Physiol 298: F1152-F1161, 2010. First published February 10, 2010; doi:10.1152/ajprenal.00499.2009.-Claudin-16 (CLDN16) is critical for renal paracellular epithelial transport of Ca2+ and Mg2+ in the thick ascending loop of Henle. To gain novel insights into the role of CLDN16 in renal Ca2+ and Mg2+ 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 Ca2+, compensatory mechanisms like parathyroid hormone and 1,25(OH)(2)D-3 were significantly elevated. Also, gene expression profiling revealed transcriptional upregulation of several Ca2+ and Mg2+ transport systems including Trpv5, Trpm6, and calbindin-D9k. Induced gene expression was also seen for thew transcripts of two putative Mg2+ 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 Ca2+ and Mg2+ homeostasis and that CLDN16-deficient mice represent a useful model to further elucidate pathways involved in renal Ca2+ and Mg2+ handling.