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

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.

WNK4 limits distal calcium losses following acute furosemide treatment.

The distal nephron is essential for calcium homeostasis. This is evidenced by disordered calcium transport following disrupted distal nephron function occurring in salt-wasting tubulopathies or with diuretic use. A plethora of studies support a role for WNK4 in thick ascending limb (TAL) and distal convoluted tubule ion transport with most studies focusing on sodium transport.

Renal COP9 Signalosome Deficiency Alters CUL3-KLHL3-WNK Signaling Pathway.

Background: The familial hyperkalemic hypertension (FHHt) cullin 3 (CUL3) mutant does not degrade WNK kinases normally, thereby leading to thiazide-sensitive Na-Cl cotransporter (NCC) activation. CUL3 mutant (CUL39) does not bind normally to the COP9 signalosome (CSN), a deneddylase involved in regulating cullin-RING ligases. CUL39 also caused increased degradation of the CUL3-WNK substrate adaptor kelch-like 3 (KLHL3).