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This rare disease occurs by loss\u2010of\u2010function mutations in CLDN16 or CLDN19 genes, causing impaired paracellular reabsorption of divalent cations along the cortical thick ascending limb (cTAL). Only partial compensation takes place in the ensuing late distal convoluted tubule, connecting tubule, and collecting duct, where the luminal transient receptor potential channel V5 (TRPV5), as well as basolateral plasma membrane calcium ATPase (PMCA) and sodium\u2010potassium exchanger (NCX1) mediate transcellular Ca<jats:sup>2+<\/jats:sup> reabsorption. The loop diuretic furosemide induces compensatory activation in these distal segments. Normally, furosemide enhances urinary calcium excretion via inhibition of the aforementioned cTAL. As Ca<jats:sup>2+<\/jats:sup> reabsorption in the cTAL is already severely impaired in FHHNC patients, furosemide may alleviate hypercalciuria in this disease by activation of the distal transcellular Ca<jats:sup>2+<\/jats:sup> transport proteins.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Cldn16\u2010deficient mice (Cldn16<jats:sup>\u2212\/\u2212<\/jats:sup>) served as a FHHNC model. Wild\u2010type (WT) and Cldn16<jats:sup>\u2212\/\u2212<\/jats:sup> mice were treated with furosemide (7\u2009days of 40\u2009mg\/kg bw) or vehicle. We assessed renal electrolyte handling (metabolic cages) and key divalent transport proteins.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Cldn16<jats:sup>\u2212\/\u2212<\/jats:sup> mice show higher Ca<jats:sup>2+<\/jats:sup> excretion than WT and compensatory stimulation of Cldn2, TRPV5, and NCX1 at baseline. Furosemide reduced hypercalciuria in Cldn16<jats:sup>\u2212\/\u2212<\/jats:sup> mice and enhanced TRPV5 and PMCA levels in Cldn16<jats:sup>\u2212\/\u2212<\/jats:sup> but not in WT mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Furosemide significantly reduces hypercalciuria, likely via upregulation of luminal and basolateral Ca<jats:sup>2+<\/jats:sup> transport systems in the distal nephron and collecting duct in this model for FHHNC.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.13927","type":"journal-article","created":{"date-parts":[[2023,1,6]],"date-time":"2023-01-06T10:15:53Z","timestamp":1673000153000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Furosemide rescues hypercalciuria in familial hypomagnesaemia with hypercalciuria and nephrocalcinosis 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