Calcium-sensing receptor mediates interleukin-1ß-induced collagen expression in mouse collecting duct cells.

The mechanisms that underlie the profibrotic effect of interleukin (IL)-1ß are complicated and not fully understood. Recent evidence has suggested the involvement of the calcium-sensing receptor (CaSR) in tubular injury. Therefore, the current study aimed to investigate whether CaSR mediates IL-1ß-induced collagen expression in cultured mouse inner medullary collecting duct cells (mIMCD3) and to determine the possible downstream signaling effector. The results showed that IL-1ß significantly upregulated the expression of type I and III collagens in a concentration- and time-dependent manner. Moreover, CaSR was expressed in mIMCD3 cells, and its expression was increased by increasing the concentrations and times of IL-1ß treatment. Selective inhibitors (Calhex231 or NPS2143) or the siRNA of CaSR attenuated the enhanced expression of type I and III collagens. Furthermore, IL-1ß increased nuclear ß-catenin protein levels and decreased cytoplasmic ß-catenin expression in cells. In contrast, blockage of CaSR by the pharmacological antagonists or siRNA could partially attenuate such changes in the IL-1ß-induced nuclear translocation of ß-catenin. DKK1, an inhibitor of ß-catenin nuclear translocation, further inhibited the expression of type I and III collagens in cells treated with IL-1ß plus CaSR antagonist. In summary, these data demonstrated that IL-1ß-induced collagen I and III expressions in collecting duct cells might be partially mediated by CaSR and the downstream nuclear translocation of ß-catenin.