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 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)2D3 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 the tra...