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lüll Mechanisms for hypercalciuria in pseudohypoaldosteronism type II-causing WNK4 knock-in mice Yang SS; Hsu YJ; Chiga M; Rai T; Sasaki S; Uchida S; Lin SHEndocrinology 2010[Apr]; 151 (4): 1829-36The mechanisms underlying hypercalciuria in pseudohypoaldosteronism type II (PHAII) caused by WNK4 mutations remain unclear. In this study, we used Wnk4(D561A/+) knock-in mice as a model of human PHAII for investigating the pathogenesis of hypercalciuria in PHAII. Serum and urine biochemistries were obtained from Wnk4(+/+) and Wnk4(D561A/+) littermates. Expression of the epithelial Ca(2+) channels [transient receptor potential channel vanilloid subtype 5 (TRPV5) and TRPV6] and calbindin-D28k (CBP-D28k) in the distal nephron and two upstream Na(+) transporters, Na(+)/H(+) exchanger 3 and Na(+)-K(+)-2Cl(-) cotransporter 2 involved in paracellular Ca(2+) reabsorption, were examined by real-time PCR, immunofluorescent staining, and immunoblotting. Compared with Wnk4(+/+) littermate controls, Wnk4(D561A/+) mice manifested hypercalciuria despite no significant differences in serum creatinine, ionized Ca(2+), PTH, and 1,25 hydroxylvitamin D(3) levels. There was no significant difference in TRPV5 expression, but a significant increase in TRPV6 and CBP-D28k was observed in Wnk4(D561A/+) mice. Despite no significant change in Na(+)/H(+) exchanger 3 expression, Na(+)-K(+)-2Cl(-) cotransporter 2 expression was significantly attenuated and urine Ca(2+) excretion rate in response to furosemide was blunted in Wnk4(D561A/+) mice. Decreased Ca(2+) reabsorption in the upstream nephron, especially in the thick ascending loops of Henle, with a secondary adaptive increase in TRPV6 and CBP-D28k expression in the distal tubules might be involved in the hypercalciuria of PHAII.|Animals[MESH]|Blotting, Western[MESH]|Calbindin 1[MESH]|Calbindins[MESH]|Calcifediol/blood[MESH]|Calcium Channels/genetics/metabolism[MESH]|Creatinine/blood[MESH]|Fluorescent Antibody Technique[MESH]|Hypercalciuria/*etiology/genetics/metabolism[MESH]|Ion Transport/genetics[MESH]|Mice[MESH]|Mice, Transgenic[MESH]|Nephrons/*metabolism[MESH]|Parathyroid Hormone/blood[MESH]|Protein Serine-Threonine Kinases/*genetics[MESH]|Pseudohypoaldosteronism/*complications/genetics/metabolism[MESH]|Reverse Transcriptase Polymerase Chain Reaction[MESH]|S100 Calcium Binding Protein G/genetics/metabolism[MESH]|Sodium-Hydrogen Exchanger 3[MESH]|Sodium-Hydrogen Exchangers/genetics/metabolism[MESH]|Sodium-Potassium-Chloride Symporters/genetics/metabolism[MESH]|Solute Carrier Family 12, Member 1[MESH]|TRPV Cation Channels/genetics/metabolism[MESH] |