THP deficiency led to reduced apical targeting of Naϩ/Kϩ/2Cl-cotransporter (NKCC2) in TAL cells and failure of THP KO mice to respond to furosemide (which targets NKCC2). In contrast, old THP KO mice had significantly less 24-hour urine volume and higher urine super-saturation than age-matched wild-type controls. Serum cystatin C was significantly higher and inulin and creatinine clearance was significantly lower in old THP KO mice than in old wild-type controls, suggesting reduced GFR in the old THP KO mice. While old THP KO remained unresponsive to furosemide, they were highly responsive to acetazolamide, suggesting a compensatory increase of water reabsorption by PCT in old THP KO mice.CONCLUSIONS: A marked decrease of GFR and a compensatory increase of water reabsorption in PCT triggered by a TAL-PCT crosstalk lead to low urine volume and supersaturation of urine constituents including hydroxyapatite in the THP KO mice, thus forming the basis of age-dependent intra-renal calcinosis.
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