Vitamin D Receptor and Interaction with DNA: From Physiology to Chronic Kidney Disease

Abstract

The biologically most active vitamin D metabolite, 1,25-dihydroxyvitamin D3 [calcitriol or 1,25(OH)2D3] exerts the vast majority of its classical actions and attributed “non-traditional” effects by means of interaction with the vitamin D receptor (VDR). Here, we review the VDR structure and function, as well as the molecular actions of vitamin D mediated via this classical endocrine receptor. We also describe the interactions of the 1,25(OH)2D3/VDR complex with the retinoid X receptor, VDR coregulators (coactivators and corepressors) and the vitamin D-response element, whereby the expression of many 1,25(OH)2D3–responsive genes is positively or negatively controlled in many different tissues through complex conformational changes. On the other hand, chronic kidney disease (CKD) may be considered “a disease of dysfunctional receptors” since CKD has been associated with resistance to the action of many hormones including 1,25(OH)2D3. CKD and uremic toxins interfere not only with 1,25(OH)2D3 metabolism but also with various VDR processes such as basal VDR synthesis, binding and function. In view of the ubiquitous nature of VDR, several VDR activators are being developed with the aim of achieving an improved biological profile for a therapeutic application in one of the pleiotropic functions of the natural hormone, while avoiding untoward effects including excessive calcium and phosphate loading. However, randomized clinical trials are required to confirm all the proposed cardiovascular and survival benefits of the old and new VDR activators.