Figure 6

Working model of the cross-talk between PC2 and CFTR in the KV inflation. (A) As in kidney cysts, we extrapolate that in WT KV epithelial cells, once stimulated by the luminal fluid-flow, PC2 raises intracellular Ca²⁺ transients. These should maintain the basal intracellular levels of cAMP, through regulation of Ca²⁺-dependent adenylyl cyclases (ACs) and phosphodiesterases (PDEs). cAMP is required for the normal rate of CFTR activity. This ensures the CFTR-mediated transport of Cl⁻ and subsequent movement of water into the KV lumen, allowing its inflation. Additionally, cAMP levels are also dependent on V2R since we know that its pharmacological inhibition by 100 µM tolvaptan impairs the KV inflation. (B) The knockdown of pkd2 changes several variables of the KV: volume enlargement [27], different cell shapes [27] and, therefore, different architectures with the consequent loss of the anterior cilia cluster [27,34], shorter cilia [34], and weakened and homogeneous luminal flow [34]. The lack of PC2 should lower the intracellular levels of Ca²⁺, which, through still unknown mechanisms, leads to a significant increase of CFTR expression at the apical region of the cell (membrane and subapical zone), namely in the anterior part of the KV. This justifies the CFTR-mediated KV enlargement observed upon lack of PC2. It is still unknown if the resulting raise in the cAMP levels, induced by the low Ca²⁺ levels, further potentiates the CFTR activity. However, mimicking a kidney cyst, pharmacological inhibition of KV V2R by 100 µM tolvaptan was enough to rescue the KV enlargement of these embryos.