Model to explain hypercalciuria and hyperphosphaturia in Dent disease. (A) Alterations in vitamin D metabolism. Parathyroid hormone (PTH) is filtered into the primary urine from which it is normally cleared by megalin-mediated endocytosis and subsequent degradation. The impaired endocytosis due to a disruption of ClC-5 results in an increased luminal PTH concentration that leads to an enhanced activation of luminal PTH receptors (PTH-R). This stimulates the transcription of the mitochondrial enzyme 1α-hydroxylase (1α-HYD) that catalyzes the conversion of the vitamin D precursor 25(OH)-VitD₃ into the active metabolite 1,25(OH)₂-VitD₃. Increased enzyme activity would be expected to lead to an increased production of 1,25(OH)₂-VitD₃ that in turn would indirectly cause hypercalciuria by stimulating intestinal Ca²⁺ reabsorption. However, 25(OH)-VitD₃ (bound to its binding protein DBP) is mainly taken up apically by megalin- and ClC-5_dependent endocytosis. Hence, the endocytosis defect in Dent disease leads to a decreased availability of the substrate for 1α-HYD. Thus there is a delicate balance between enzyme activation and precursor scarcity that can turn toward decreased as well as increased production of 1,25(OH)₂-VitD₃. Furthermore, the active hormone is also lost into the urine. This may account for the variability of hypercalciuria observed in Dent disease patients as well as in ClC-5 KO mouse models. (B) Mechanism causing phosphaturia. The apical Na phosphate cotransporter NaPi-2a is regulated by PTH, which causes its endocytosis and degradation. The increased stimulation of apical PTH receptors that is due to the increased luminal PTH concentration caused by an impaired endocytosis of PTH in the absence of ClC-5 leads to less NaPi-2a in the apical membrane, resulting in a urinary loss of phosphate.