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Molecular Biology of Vitamin D: Genomic and Nongenomic Actions of Vitamin D in Chronic Kidney Disease

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Vitamin D in Chronic Kidney Disease

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Abstract

Chronic kidney disease (CKD) progression is characterized by features of accelerated aging (bone loss, increased propensity for fractures and vascular calcification, hypertension and cardiovascular disease) and a risk of mortality 20- to 30-fold higher than in age- and gender-matched individuals with normal renal function. The progressive loss of renal capacity to maintain the functional integrity of the vitamin D endocrine system is a main determinant of the severe pro-aging features that reduce survival. The goal of this chapter is an update of the progress of the last 5 years in our understanding of the molecular pathophysiology underlying CKD-induced abnormalities in: (a) Systemic and local vitamin D bioactivation to its hormonal form, 1,25-dihydroxyvitamin D or calcitriol; (b) Classical genomic and non-genomic actions of the calcitriol/vitamin D receptor (VDR) complex that compromise survival, and (c) Synergistic VDR activation by calcitriol and its precursor, 25-hydroxyvitamin D, to counteract VDR reductions.

Special focus is directed to the molecular bases supporting the paradigm switch to maximize calcitriol/VDR anti-aging actions. Specifically, from suppression of the PTH gene to attenuate the bone loss predisposing to vascular calcification, to the induction of the FGF23 and α-klotho genes to simultaneously control the pro-aging effects of hyperphosphatemia and of an excess of active vitamin D, while maintaining the plethora of anti-aging/pro-survival actions of renal and circulating klotho. Special attention is also directed into calcitriol/VDR distinct control of Wnt/β-catenin signals to promote mineralization in bone while preventing calcification in the vasculature, and into the emerging fields of calcitriol/VDR regulation of microRNA synthesis and klotho-independent anti-aging actions. This mechanistic knowledge is a mandatory first step to evaluate the accuracy of current biomarkers of disease severity and response to therapy.

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Acknowledgements

This work was supported by grants from Plan Estatal de I+D+i 2013–2016, Instituto de Salud Carlos III (ISCIII)-Fondo Europeo de Desarrollo Regional (FEDER) (PI14/01452), Plan de Ciencia, Tecnología e Innovación 2013–2017 del Principado de Asturias (GRUPIN14-028), Fundación para el Fomento en Asturias de la Investigación Científica Aplicada y la Tecnología (FICYT), Instituto Reina Sofía de Investigación Nefrológica, Fundación Renal Íñigo Álvarez de Toledo, Red de Investigación Renal-RedInRen from ISCIII (RD06/0016/1013, RD12/0021/1023), and by Sociedad Asturiana Fomento Investigaciones Metabólicas (SAFIM).

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  1. Bone and Mineral Research Unit, Instituto Reina Sofía de Investigación Nefrológica, REDinREN del ISCIII, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain

    Adriana S. Dusso PhD

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  1. Adriana S. Dusso PhD
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Correspondence to Adriana S. Dusso PhD .

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  1. Ramsay-Générale de Santé, Clinique du Landy, Saint Ouen, France

    Pablo A. Ureña Torres

  2. San Paolo Hospital, DiSS University of Milan, Milan, Italy

    Mario Cozzolino

  3. VU University Medical Center, Amsterdam, The Netherlands

    Marc G. Vervloet

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Dusso, A.S. (2016). Molecular Biology of Vitamin D: Genomic and Nongenomic Actions of Vitamin D in Chronic Kidney Disease. In: Ureña Torres, P., Cozzolino, M., Vervloet, M. (eds) Vitamin D in Chronic Kidney Disease. Springer, Cham. https://doi.org/10.1007/978-3-319-32507-1_3

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