Downregulation of Ca2+ and Mg2+ Transport Proteins in the Kidney Explains Tacrolimus (FK506)-Induced Hypercalciuria and Hypomagnesemia

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Abstract
FK506 (tacrolimus) and dexamethasone are potent immunosuppressants known to induce significant side effects on mineral homeostasis, including hypercalciuria and hypomagnesemia. However, the underlying molecular mechanisms remain unknown. The present study investigated the effects of FK506 and dexamethasone on the expression of proteins involved in active Ca2+ reabsorption: the epithelial Ca2+ channel TRPV5 and the cytosolic Ca2+-binding protein calbindin-D28K. In addition, the renal expression of the putative Mg2+ channel TRPM6, suggested to be involved in transcellular Mg2+ reabsorption, was determined. Administration of FK506 to rats by daily oral gavage during 7 d significantly enhanced the urinary excretion of Ca2+ and Mg2+ and induced a significant hypomagnesemia. FK506 significantly decreased the renal mRNA expression of TRPV5 (62 ± 7% relative to controls), calbindin-D28K (9 ± 1%), and TRPM6 (52 ± 8%), as determined by real-time quantitative PCR analysis. Furthermore, semiquantitative immunohistochemistry showed reduced renal protein abundance of TRPV5 (24 ± 5%) and calbindin-D28K (29 ± 4%), altogether suggesting that downregulation of these transport proteins is responsible for the FK506-induced Ca2+ and Mg2+ wasting. In contrast, dexamethasone significantly enhanced renal TRPV5 (150 ± 15%), calbindin-D28K (177 ± 23%), and TRPM6 (156 ± 20%) mRNA levels along with TRPV5 (211 ± 8%) and calbindin-D28K (176 ± 5%) protein abundance in the presence of significantly increased Ca2+ and Mg2+ excretion. This indicated that these proteins are directly or indirectly regulated by dexamethasone. In conclusion, FK506 and dexamethasone induce renal Ca2+ and Mg2+ wasting, albeit by different mechanisms. Downregulation of specific Ca2+ and Mg2+ transport proteins provides a molecular mechanism for FK506-induced hypercalciuria and hypomagnesemia, whereas dexamethasone positively regulates these proteins.

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