Evidence for the impairment of the vitamin D activation pathway by cyclosporine A

Abstract

Cyclosporine A (CsA) is a potent immunosuppressant with the drawback of renal side effects. We reported that CsA markedly decreases calcium-binding protein calbindin-D28k mRNA levels in rat kidneys, and showed that this decrease is associated with its adverse renal effects. The transcription of the calbindin-D28k gene is activated via the vitamin D pathway. In this work, the potential CsA-mediated impairment of the vitamin D pathway was investigated. Wistar rats were treated for 12 days with 50 mg/kg/day CsA or for 20 days with 50 mg/kg/day of the non-immunosuppressant and non-nephrotoxic SDZ PSC 833, which had been previously shown not to affect calbindin-D28k mRNA levels. The expression of the three vitamin D-regulated genes calbindin-D28k, 1,25-dihydroxyvitamin D 3-24-hydroxylase (24-OHase), and vitamin D receptor (VDR) were quantified in rat kidney homogenates by real-time reverse transcription–polymerase chain reaction. Plasma parathyroid hormone (PTH) as well as plasma and kidney 1,25 dihydroxyvitamin D 3 (calcitriol) levels were monitored in all animals. CsA induced a 85% decrease in calbindin-D28k mRNA levels as well as a 40% and 69% decrease in VDR and 24-OHase mRNA levels, respectively. Plasma and kidney 1,25 dihydroxyvitamin D 3 as well as plasma PTH levels were increased by CsA, but not by SDZ PSC 833. The treatment with SDZ PSC 833 did not affect calbindin-D28k or VDR expression, but did cause a 73% decrease in 24-OHase mRNA levels. Taken together, these results indicate an association between CsA-mediated down-regulation of rat renal calbindin-D28k mRNA and the decrease in other 1,25 dihydroxyvitamin D 3-regulated genes, suggesting an impairment of the vitamin D pathway by CsA which may be related to its adverse renal side effects and its immunosuppressive activity.