NDT Advance Access originally published online on February 13, 2007
Nephrology Dialysis Transplantation 2007 22(4):1033-1040; doi:10.1093/ndt/gfl817
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Ciclosporin reduces paracellin-1 expression and magnesium transport in thick ascending limb cells
1Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan and 2Kidney Research Institute, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taipei, Taiwan
Correspondence and offprint requests to: Mai-Szu Wu, Division of Nephrology, Chang Gung Memorial Hospital, 222, Mai-Chin Road, Keelung, Taiwan. Email: maxwu1{at}adm.cgmh.org.tw
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Abstract |
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Background. Renal magnesium (Mg2+) wasting is one of the ciclosporin (CsA) tubular effects. The major site of Mg2+ transport is the thick ascending limb (TAL), where 70% of the ultrafiltrable Mg2+ is reabsorbed paracellularly. Paracellin-1 is a tight junction protein, which regulates the paracellular Mg2+ transport in the TAL. We hypothesize that CsA reduces the expression and function of paracellin-1 and accounts for the observed renal Mg2+ wasting.
Methods. We established an immortalized cultured cortical TAL (cTAL) cell line from L-PK/Tag1 transgenic mice by microdissection. The cultured cells expressed paracellin-1 and the characteristics of cTAL cells. Real-time PCR and western blotting were used to test the CsA effects on paracellin-1 expression of cultured cTAL cells. Cytosolic-free Mg2+ concentration [Mg2+]i change with time in a single cTAL cell was used as an indicator of transcellular Mg2+ transport and assessed by using fluorescence dye Mag-fura-2 AM. Paracellular Mg2+ transport was measured by cells grown in porous filters.
Results. The results showed that CsA significantly reduced paracellin-1 mRNA and protein expression in a dose-dependent manner. CsA (100 ng/ml) incubation for 24 h induced a decrease of paracellin-1 mRNA by 89.4% and paracellin-1 protein by 75.4%. CsA (100 ng/ml) did not change transcellular Mg2+ transport, but paracellular Mg2+ transport was decreased in CsA-treated cTAL cells by 74.4%.
Conclusion. These results suggested that reduced PCLN-1 expression and paracellular Mg2+ transport might play a role in the renal Mg2+ wasting in the CsA tubular effect.
Keywords: ciclosporin; magnesium transport; paracellin-1; PCLN-1; thick ascending limb
Received for publication: 27. 6.06
Accepted in revised form: 18.12.06
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