Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020438 (hypercalciuria)
 2,502 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 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.
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PMID:Mechanisms for hypercalciuria in pseudohypoaldosteronism type II-causing WNK4 knock-in mice. 2018 99