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Background  Hypercalciuria can result from activation of the basolateral calcium-sensing receptor (CaSR), which in the thick ascending limb of Henle’s loop controls Ca 2+  excretion and NaCl reabsorption in response to extracellular Ca 2+ . However, the function of CaSR in the regulation of NaCl reabsorption in the distal convoluted tubule (DCT) is unknown. We hypothesized that CaSR in this location is involved in activating the thiazide-sensitive NaCl cotransporter (NCC) to prevent NaCl loss.   Methods  We used a combination of  in vitro  and  in vivo  models to examine the effects of CaSR on NCC activity. Because the KLHL3-WNK4-SPAK pathway is involved in regulating NaCl reabsorption in the DCT, we assessed the involvement of this pathway as well.   Results  Thiazide-sensitive  22 Na +  uptake assays in  Xenopus laevis  oocytes revealed that NCC activity increased in a WNK4-dependent manner upon activation of CaSR with Gd 3+ . In HEK293 cells, treatment with the calcimimetic R-568 stimulated SPAK phosphorylation only in the presence of WNK4. The WNK4 inhibitor WNK463 also prevented this effect. Furthermore, CaSR activation in HEK293 cells led to phosphorylation of KLHL3 and WNK4 and increased WNK4 abundance and activity. Finally, acute oral administration of R-568 in mice led to the phosphorylation of NCC.   Conclusions  Activation of CaSR can increase NCC activity  via  the WNK4-SPAK pathway. It is possible that activation of CaSR by Ca 2+  in the apical membrane of the DCT increases NaCl reabsorption by NCC, with the consequent, well known decrease of Ca 2+  reabsorption, further promoting hypercalciuria.

The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway