Question:

Carbon monoxide (CO) tightly binds to cytochromes and hemoglobin and thus interferes with cytochrome dependent cellular functions as well as oxygen transport in blood. CO is released from CO releasing molecules (CORM) including tricarbonyl-dichlororuthenium (II) dimer (CORM-2), molecules considered for the treatment of several clinical disorders including vascular dysfunction, inflammation, tissue ischemia and organ rejection. Cytochrome 450-sensitive functions include the formation of 1,25(OH)₂D₃ by the renal 25-hydroxyvitamin D₃ 1-alpha-hydroxylase (Cyp27b1). The enzyme is further regulated by PTH, FGF23 and Klotho. 1,25(OH)₂D₃ is in turn a powerful regulator of Ca²⁺ and phosphate transport as well as Klotho expression. The present study thus explored, whether CORM-2 influences 1,25(OH)₂D₃ formation and Klotho expression in the mice.

Methods:

Plasma 1,25(OH)₂D₃, and FGF23 concentrations were determined by ELISA, serum phosphate, calcium and creatinine concentrations by colorimetric methods, renal gene expressions by quantitative RT-PCR and Klotho protein expression by western blotting.

Results:

CORM-2 injection markedly down-regulated 1,25(OH)₂D₃ plasma levels and Cyp27b1 gene expression with significantly affecting FGF23 plasma levels. CORM-2 further decreased renal Klotho protein abundance and gene expression without significantly modifying plasma phosphate concentration as well as plasma Ca²⁺ concentration.

Conclusions:

CORM-2 injection reduces 1,25(OH)₂D₃ synthesis and Klotho expression in the kidney.