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2020 ; 8
(1
): e14316
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Tacrolimus-induced hypomagnesemia and hypercalciuria requires FKBP12 suggesting a
role for calcineurin
#MMPMID31908154
Gratreak BDK
; Swanson EA
; Lazelle RA
; Jelen SK
; Hoenderop J
; Bindels RJ
; Yang CL
; Ellison DH
Physiol Rep
2020[Jan]; 8
(1
): e14316
PMID31908154
show ga
Calcineurin 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 previously 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 mRNA abundance of key magnesium and calcium transport proteins (NCX-1
and Calbindin-D(28k) ). However, qPCR also showed decreased mRNA expression of
NCX-1 and Calbindin-D(28k) , and TRPM6. In contrast, KS-FKBP12(-/-) mice treated
with tacrolimus were completely protected from these effects. These results
indicate that tacrolimus affects calcium and magnesium transport along the distal
convoluted tubule and strongly suggests that inhibition of the phosphatase,
calcineurin, is directly involved.
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