FKBP12 Kidney‐Specific Knockout Mice are Protected from Tacrolimus‐Induced Hypertension

Tacrolimus, a widely used immunosuppressive drug, causes hypertension and disrupts diurnal blood pressure dipping, accelerating cardiovascular disease. We showed previously that tacrolimus activates the thiazide‐sensitive NaCl cotransporter to raise blood pressure, but it was not clear if this was due to direct effects of tacrolimus in the kidney. Here we test the hypothesis that the same mechanism by which tacrolimus suppresses the immune system, binding to FKBP12 and then inhibiting calcineurin, occurs in renal epithelial cells to cause hypertension. Using the Pax8/rtTA CRE/LOX system, we generated mice in which FKBP12 could be deleted from renal epithelial cells (FKBP12‐KS‐KO). We measured blood pressure by radiotelemetry,at baseline and during 3 weeks of tacrolimus treatment (3 mg/kg sc), to test whether FKBP12 disruption alone, or calcineurin inhibition via tacrolimus, affects blood pressure. At baseline, FKBP12‐KS‐KO mice had blood pressures and dipping patterns similar to wild type littermates (WT). Tacrolimus treatment raised blood pressure in WT mice and abrogated diurnal dipping. FKBP12‐KS‐KO mice, in contrast, had lower daytime systolic blood pressures (2 way ANOVA; p<0.0001) and maintained their dipping patterns (2 way ANOVA; p=0.0023) relative to WT animals. Hypertension and loss of diurnal dipping result directly from calcineurin inhibition along the nephron, not from direct interference with FKBP12. As calcineurin inhibition mediates the therapeutic effects of these drugs, tissue specificity will likely be necessary to avoid causing side effects of novel calcineurin inhibitors. NIH, AHA