IMPAIRMENT OF AQP2 TARGETING IN RESPONSE TO VASOPRESSIN IN HYPERCALCI- URIC PATIENTS: EVIDENCE FOR EXTRACELLULAR CALCIUM ACTING AS FIRST MESSENGER

Disturbances in renal concentrating ability have been associated with hypercalciuria in humans and experimental animals. In a previous work we have shown that extracellular calcium, possibly acting through Calcium Sensing Receptor (CaR) signaling, antagonizes forskolin-induced AQP2 translocation in renal cells. To test the hypothesis that increased urinary calcium inhibits AQP2 targeting in response to vasopressin in humans, in this study we evaluated AQP2 excretion in hypercalciuric children after 1-deamino-arginin-vasopressin (dDAVP) administration. Normocal- ciuric children served as control. Urine osmolarity and AQP2 excretion were measured in urine samples obtained hourly after 10 mg (if weight < 10 Kg) or 20 mg dDAVP administration in- tranasaly from children (mean age of 8.4±1.2 years) enrolled in the study. Based on their response to dDAVP, children were considered normal or poor responders. Among them, some children were hypercalciuric defined by a Ca/Creat ratio > 0.2 on 3 separate samples. AQP2 excretion in urine samples was measured by Enzyme-Linked immunosorbent assay (ELISA). In the group of normocalciuric children having normal urinary concentration ability, dDAVP ad- ministration resulted in a significant increase in urine osmolality (1110±32 mOsm/l at peak, n=19) associated with a significant increase in urinary AQP2 excretion (from 250±80 fmol/mg Creat be- fore to 467±113 after dDAVP treatment, P<0.0001). In contrast, in hypercalciuric children AQP2 excretion did not significantly increase in response to dDAVP administration either in the group displaying normal urinary concentration ability (AQP2 excretion from 291±58.9 fmol/mg Creat before to 291±77 after dDAVP treatment, urine osmolarity 1018±32 mOsm/l at peak, n=13). and in the group having poor urinary concentration ability (AQP2 excretion from 432±117 fmol/mg Creat before to 391±80 after dDAVP test, urine osmolality 512±104 mOsm/l at peak, n=12). The obtained data demonstrate that in hypercalciuria AQP2 excretion in response to vasopressin is reduced or abolished. This effect was observed in both normal and poor responders. These data would support the hypothesis that increased urinary calcium levels inhibits AQP2 targeting in re- sponse to vasopressin in humans possibly through activation of CaR signaling. In hypercalciuric patients the impairment of AQP2 targeting observed in response to vasopressin may contribute to reduce the risk of an increased incidence stone formation during antidiuresis.