Vitamin D receptor: Mechanisms for vitamin D resistance in renal failure

1,25-dihydroxyvitamin D [1,25(OH)₂D₃], the hormonal form of vitamin D, controls serum levels of parathyroid hormone (PTH) and parathyroid hyperplasia. Both 1,25(OH)₂D₃ actions involve regulation of gene transcription by the 1,25(OH)₂D₃/vitamin D receptor (VDR) complex. In advanced renal failure, in addition to low serum 1,25(OH)₂D₃ and reduced parathyroid vitamin D receptor content, several mechanisms downstream from 1,25(OH)₂D₃/VDR complex formation contribute to the impairment of 1,25(OH)₂D₃ action, including reduced levels of the retinoid X receptor, RXR, with the consequent reduction in VDR/RXR heterodimer formation, and accumulation of uremic toxins and increases in nuclear levels of calreticulin, two processes that impair the binding of the VDR/RXR complex to vitamin D responsive elements in vitamin D-regulated genes. VDR/RXR-heterodimer formation and its binding to DNA is critical for 1,25(OH)₂D₃ regulation of gene transcription. Early interventions with 1,25(OH)₂D₃ could delay the onset of vitamin D resistance by preventing both 1,25(OH)₂D₃ deficiency and its critical consequence, reduction in VDR content. Once established, vitamin D resistance could be counteracted by vitamin D analogs. While their less calcemic properties make higher dosing safer, their specificity to recruit co-activator molecules to the transcriptional pre-initiation complex could compensate for reduced 1,25(OH)₂D₃/VDR by potentiating VDR-transactivation/transrepression of genes critical for normal PTH synthesis and parathyroid cell growth.