Tacrolimus ‐induced hypomagnesemia and hypercalciuria requires FKBP12 suggesting a role for calcineurin

We showed that deletion of the tacrolimus ‐binding protein, necessary for tacrolimus to inhibit calcineurin, completely prevented the effects on divalent ion metabolism. This was associated with protection of transport proteins in the distal convoluted tubule. AbstractCalcineurin inhibitors (CNIs) are immunosuppressive drugs used to prevent graft rejection after organ transplant. Common side effects include renal magnesium wasting and hypomagnesemia, which may contribute to new ‐onset diabetes mellitus, and hypercalciuria, which may contribute to post‐transplant osteoporosis. Previous work suggested that CNIs reduce the abundance of key divalent cation transport proteins, expressed along the distal convoluted tubule, causing renal magnesium and calcium wasting. It has not been clear, however, whether these effects are specific for the distal convoluted tubule, and whether these represent off‐target toxic drug effects, or result from inhibition of calcineurin. The CNI tacrolimus can inhibit calcineurin only when it binds with the immunophilin, FKBP12; we previou sly generated mice in which FKBP12 could be deleted along the nephron, to test whether calcineurin inhibition is involved, these mice are normal at baseline. Here, we confirmed that tacrolimus‐treated control mice developed hypomagnesemia and urinary calcium wasting, with decreased protein and mRN A abundance of key magnesium and calcium transport proteins (NCX‐1 and Calbindin‐D28k). However, qPCR also sh...
Source: Physiological Reports - Category: Physiology Authors: Tags: ORIGINAL RESEARCH Source Type: research