Editorial over the Many Faces of Vitamin D in Chronic Kidney Disease: from Mineral to Immune-Inflammatory Modulator
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EDITORIAL
Editorial over the Many Faces of Vitamin D in Chronic Kidney Disease: from Mineral to Immune-Inflammatory Modulator Patrick M. Honore1,2 and Herbert D. Spapen1 Vitamin D (vit D), whether produced in the skin or absorbed from the diet, is first metabolized in the liver to generate 25-hydroxyvitamin D (25OHD) and then hydroxylated in the proximal renal tubule to 1,25dihydroxyvitamin D (1,25(OH) 2 D). 1,25(OH) 2 D (calcitriol) is the major biologically active metabolite and serves a paracrine/autocrine function. 1,25(OH)2D forms a complex with the vit D nuclear receptor which binds to vit D response elements in the deoxyribonucleic acid (DNA). Thousands of these binding sites regulate hundreds of genes creating a multitude of genomic effects that modulate cell activation, proliferation, and differentiation within the immune-inflammatory system [1]. This underpins the biological rationale for a potential beneficial partnership of vit D in a variety of immune-inflammatory conditions that largely transcends its undisputed regulatory role in calcium/phosphate homeostasis and bone mineralization [2, 3]. Chronic kidney disease (CKD) is an intricate pathology characterized by a state of accelerated cardiovascular deterioration. Persistent inflammation has been recognized as an important component of CKD and may in part account for cardiovascular and all-cause mortality [4]. Low levels of both 25OHD and 1,25(OH)2D are observed in patients with CKD and are associated with higher mortality and faster progression of kidney disease [5]. In a recent issue of Inflammation, Zhao et al. showed that calcitriol significantly reduced tubulo-interstitial inflammation in a rodent renal injury model [6]. The authors linked this renoprotective effect to calcitriol-induced up1
ICU Department, Universitair Ziekenhuis Brussels, Vrije Universiteit Brussel, 101 Laarbeeklaan, 1090 Brussels, Jette, Belgium 2 To whom correspondence should be addressed at ICU Department, Universitair Ziekenhuis Brussels, Vrije Universiteit Brussel, 101 Laarbeeklaan, 1090 Brussels, Jette, Belgium. E-mail: [email protected]
regulation of zinc finger protein A20, a de-ubiquitinating enzyme which causes disruption of nuclear factor kappa B (NF-κB) dependent intracellular chemo- and cytokine production and suppresses apoptotic pathways [7]. Whether this novel compelling insight into the cellular mechanism of action of vit D may change the current or future therapeutic approach of CKD is uncertain. Factors contributing to the progression of CKD are indeed not limited to perturbed mineral metabolism, chronic inflammation, and oxidative stress but also include proteinenergy wasting, pre-existing heart failure, arterial hypertension, iron deficiency, and dialysis-related injury [8]. Patients with CKD often present a “leaky gut” and/or profound alterations in gut microbial flora. Increased gut wall permeability promotes translocation of bacteria and endotoxin which continuously fuels an inflammatory state. Changes in the intestinal microbiome are highly
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