Nephrol Dial Transplant. 2015 Sep 22. pii: gfv340. [Epub ahead of print]
Mazzaferro S1, Pasquali M2.
Cholecalciferol, the precursor of Vitamin D3, is a very old, highly conserved, molecule. Its presence is evident in non-mineralized 750 million-year-old living species, such as plankton. The more active metabolites, a receptor and a D binding protein, appear later, along with the increasing complexity of animal species living in the sea. In the sea, however, the biological function of vitamin D is unlikely to be linked with mineral metabolism, and we can hypothesize a relationship with an immune response. It is in terrestrial animals exhibiting cellular bone that the complexity of vitamin D increases. At this stage of evolution, we see the appearance of bone cells that are capable of producing hormones that regulate and are regulated by vitamin D. This interaction starts a sophisticated metabolic system that modulates both mineral and energy metabolism for the requirements of the musculoskeletal system. Among the so-called pleiotropic effects of vitamin D, those resulting from the inhibitory effect on the renin-angiotensin system are of particular interest for nephrologists. Intriguingly, however, more than for anti-hypertensive effects, this interaction could be relevant for anti-inflammatory actions, possibly representative of a residual ancestral role of vitamin D. In addition, this evolutionary dynamism of the vitamin D system should not be separated from the chemical dynamism that characterizes the ligand molecule and its specific receptor. Both are capable of significant tridimensional modifications that contribute to an increase in the variability and the partial predictability of their final biological effect. A dynamic overview of this system that takes into account its evolutionary and adaptive aspects may be helpful to understand its biological complexity and to envisage why using vitamin D metabolites for therapeutic purposes is still a matter of debate.
FIGURE 5: Schematic of the so-called ‘VDR machine’. The final shape of the VDR differs according to binding of a natural vitamin D ligand (A) or of a vitamin D analogue (B). This modifies the affinity of the VDR with co-activators or co-repressor protein-complexes, thus contributing the variability of the biological response. RXR: retinoid X receptor; VDR: vitamin D receptor; VDRE: vitamin D response element.