Evidence for the impairment of the vitamin D activation pathway by cyclosporine A.
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 D3-24-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 D3 (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 D3 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 D3-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.
Grenet
O
O
Preclinical Safety, Novartis Pharma AG, Basel, Switzerland. olivier.grenet@pharma.novartis.com
Bobadilla
M
M
Chibout
S D
SD
Steiner
S
S
D000818:Animals; D016572:Cyclosporine / Q000009:adverse effects / Q000494:pharmacology*; D003524:Cyclosporins / Q000009:adverse effects / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D051437:Renal Insufficiency / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D014807:Vitamin D / Q000378:metabolism*
D003524:Cyclosporins; D007166:Immunosuppressive Agents; D018167:Receptors, Calcitriol; D014807:Vitamin D; D016572:Cyclosporine; C070272:valspodar