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

• Published in: Biochemical pharmacology 2000-02, Vol.59 (3), p.267-272
• Main Authors: Grenet, Olivier, Bobadilla, Maria, Chibout, Salah-Dine, Steiner, Sandra
• Format: Article
• Language: English
• Subjects: 1,25 dihydroxyvitamin D 3; Animals; Biological and medical sciences; Cyclosporine - adverse effects; Cyclosporine - pharmacology; cyclosporine A; Cyclosporins - adverse effects; Cyclosporins - pharmacology; Drug toxicity and drugs side effects treatment; Gene Expression - drug effects; immunosuppression; Immunosuppressive Agents - adverse effects; Immunosuppressive Agents - pharmacology; Male; Medical sciences; Pharmacology. Drug treatments; rat; Rats; Rats, Wistar; Receptors, Calcitriol - genetics; Receptors, Calcitriol - metabolism; Renal Insufficiency - chemically induced; Renal Insufficiency - genetics; Renal Insufficiency - metabolism; TaqMan RT–PCR; Toxicity: urogenital system; Vitamin D - metabolism; vitamin D pathway
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(99)00321-4

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.