A novel mouse model for determining the role of FKBP12 and calcineurin inhibition in tacrolimus‐mediated hypertension and hyperkalemia (1136.6)

The calcineurin inhibitor tacrolimus is widely used to prevent transplant organ rejection. Its use, however, is complicated by hypertension, hyperkalemia, and kidney failure. Tacrolimus suppresses the immune system by binding to an endogenous protein, FKBP12, inhibiting the phosphatase calcineurin. We reported previously that tacrolimus treatment activates the renal sodium chloride cotransporter (NCC), an event necessary to cause hypertension. It is unclear whether tacrolimus activates NCC in the kidney by 1) blocking calcineurin‐independent effects of FKBP12 or 2) inhibiting calcineurin. To address this, we used the Pax8 CRE/LOX system to delete FKBP12 from the renal tubules of mice, upon treatment with doxycycline. Kidney‐specific FKBP12 knockout alone did not increase the abundance of phosphorylated NCC (active), or cause hypertension or hyperkalemia. In contrast, phosphorylated NCC was significantly lower in FKBP12 knockout mice than in wildtype mice (un‐induced), after tacrolimus treatment. These results suggest that tacrolimus inhibition of FKBP12 does not activate NCC directly; instead the drug must bind to FKBP12 and inhibit calcineurin along the nephron to activate NCC. This implies that calcineurin inhibitors that do not bind FKBP12 retain the potential to cause hypertension and hyperkalemia. Understanding how calcineurin regulates NCC, however, may lead to safer immunosuppressive drugs. Grant Funding Source : Supported by RO1 DK095841 02