However, in studies on Takeda G protein-coupled receptor 5 (TGR5)/FXR signaling, the activation of FXR alone by CDCA or obeticholic acid (OCA, INT-747, or 6α-ethyl-chenodeoxycholic acid) does not upregulate AQP2 in a mouse model of lithium-induced nephrogenic diabetes insipidus; conversely, the activation of TGR5 by INT-777 (TGR5 agonist) or INT-767 (FXR and TGR5 dual agonist) increases AQP2 expression through the TGR5-activated cAMP-protein kinase A (PKA) signaling pathway16. This evidence concerns the gene GPBAR1 and nephrogenic diabetes insipidus.