Fig. 4.

Role of 12-kDa FK506-binding protein (FKBP12) in distal convoluted tubule (DCT) Mg²⁺ handling. NaCl cotransporter (NCC) activity and transient receptor potential channel subfamily M member 6 (TRPM6) expression under normal conditions (left) and after tacrolimus treatment (right) are shown. TRPM6 is regulated by epidermal growth factor (EGF) that is generated by cleavage from proEGF and stimulates EGF receptor (EGFR). Stimulation of EGFR promotes TRPM6 transcription via the EGF-ERK1/2- activator protein-1 (AP-1) pathway and increases cell surface protein abundance and activation. The tacrolimus-FKBP12 complex inhibits calcineurin, leading to hypertension and hypomagnesemia as a result of NCC activation and TRPM6 downregulation. Tacrolimus treatment can decrease Egf mRNA expression and transcriptional activity of AP-1, leading to TRPM6 downregulation.