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7 Vitamin D Downregulation of Pathways that Reduce Renal Klotho

7 Vitamin D Downregulation of Pathways that Reduce Renal Klotho

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67



The release of TNFα to the circulation by the increased renal ADAM17 is sufficient to explain the paricalcitol/enalapril synergy, as TNFα induces ADAM17 gene

transcription [126]. This initiates a vicious cycle for increases in renal ADAM17

and TNFα-driven systemic inflammation for klotho reductions and renal inflammatory damage that are independent of angiotensin II, and consequently, no longer

responsive to anti-RAS therapy but suppressible by active vitamin D. Indeed, calcitriol is a recognized immunomodulator, known to decrease the antigenicity of

antigen presenting cells and the production of pro-fibrotic and pro-inflammatory

Th1 cytokines while enhancing the production of anti-inflammatory Th2 cytokines.

The combination of several calcitriol/VDR actions on T cells shifts their polarization towards a Th2/regulatory phenotype and stimulates T regulatory lymphocyte

development [10, 127]. Therefore, calcitriol/VDR protection from inflammationdriven multiple organ damage could not only attenuate the reductions of renal klotho

but the accumulation of damaged DNA induced by excessive oxidative stress.



3.8



Vitamin D Direct Anti-aging Actions Unrelated

to Maintenance of Renal Klotho



The calcitriol/VDR complex also contributes to repair damaged DNA. Accumulation

of DNA damage is a main determinant of normal cellular aging and premature

senescence, which in vascular smooth muscle cells hasten atherosclerosis. Pre

Lamin A accumulation contributes to DNA damage and to impaired DNA damage

responses that accelerate calcification [128]. The loss of Lamin A in progeria and in

laminopaties associates with increases in the protease cathepsin L which, in turn,

degrades 53BP1, a protein essential for the early responses to DNA damage.

Calcitriol treatment in fibroblast deprived of Lamin A is sufficient to inhibit the

activity of the increased cathepsin L [129] and maintain nuclear levels of 53BP1 by

preventing its degradation. Therefore, effective reduction of cathepsin L activity is

a novel antiaging vitamin D action contributing to multiorgan protection.

Calcitriol upregulation of BRCA1 may also contribute to improve DNA damage

repair [130]. Thus, calcitriol/VDR actions not only attenuate the plethora of factors

accelerating damaged DNA accumulation in CKD, but also reverse in part the proaging features of already adversely affected cells.



3.9



Conclusions



One finding of the last 5 years has ended the 10-year search for the mechanisms

underlying vitamin D renal and cardiovascular protection unrelated to the control of

SHPT: “Vitamin D induction of the klotho gene” and that the loss of renal klotho

fully reproduces the accelerated aging and the short life span of global klotho

absence in mice and men. However, the accuracy of serum klotho as a unique biomarker of antiaging potential has been challenged by the identification of a process



68



A.S. Dusso



of renal transcytosis of circulating soluble klotho to the urinary space, through the

kidney. Undoubtedly, serum klotho accumulation could reflect an impaired transcytosis through a failing kidney rather than a higher renal klotho content.

The identification that increased osteoblastic Wnt inhibition, responsible for

bone mineralization defects that prompt vascular calcifications, occurs even before

elevations in serum PTH and associates to increases in TGFβ. Thus, vitamin D

induction of Wnt in osteoblasts, suppression of Wnt in the kidney and vasculature,

and VDR antagonism of adverse TGFβ/Smad signals add to the mechanisms for

vitamin D renal and vascular protection unrelated to the control of SHPT.

Vitamin D simultaneous induction of FGF23, exclusively in hyperphosphatemic

states, and of CYP24A1 adds to the induction of klotho and the suppression of PTH

to tightly control the development of hyperphosphatemia or of an excess of circulating vitamin D, which could compromise klotho survival actions. However, clinical

studies evaluating the impact of high FGF23 on the degradation of vitamin D

metabolite showed lower rather than the expected higher degradation, possibly

attributable to the lower renal megalin of CKD. Reduced megalin could also compromise soluble klotho induction of urinary phosphorus and potassium excretion.

Vitamin D induction of megalin could simultaneously reduce the risk of hyperphosphatemia while preserving sklotho actions.

Finally, we have learned of a 25(OH)D/calcitriol (analog) synergy that can effectively reverse resistant parathyroid hyperplasia and achieve a 50 % suppression of

PTH without increasing the dosage of active vitamin D, but with the simple correction of vitamin D deficiency through vitamin D supplementation. Importantly, either

monotherapy was insufficient per se to suppress PTH or parathyroid growth.

Undoubtedly, the safely and efficacy of this therapy to simultaneously maintain renal

klotho without hyperphosphatemia should be examined in prospective studies.

We have also learned that simultaneously with all local and systemic attempts to

maintain renal klotho (downregulation of hypertension and inflammation), vitamin

D induces cellular anti-aging mechanisms by repairing damaged DNA. Furthermore,

we have learned about our gap of knowledge of vitamin D control of micro-RNAs,

and their diagnostic and therapeutic potential compared to other health areas.

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

Íđigo 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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Chapter 4



Vitamin D Receptor and Interaction

with DNA: From Physiology to Chronic

Kidney Disease

Jordi Bover, César Emilio Ruiz, Stefan Pilz, Iara Dasilva,

Montserrat M. Díaz, and Elena Guillén



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.

Keywords Vitamin D • Vitamin D receptor • Chronic kidney disease • Calcitriol •

Uremia • CKD-MBD • Calcium • Phosphate • Parathyroid hormone • Hyperparathyroidism • Paricalcitol • FGF23 • Klotho • Calcidiol



J. Bover, MD, PhD (*) • C.E. Ruiz, MD • I. Dasilva, MD • M.M. Díaz, MD, PhD

E. Guillén, MD

Department of Nephrology, Fundaciò Puigvert, IIB Sant Pau, REDinREN, Barcelona, Spain

e-mail: jbover@fundacio-puigvert.es

S. Pilz, MD, PhD

Department of Endocrinology and Metabolism, Medical University of Graz,

Grazy, Styria, Austria

© Springer International Publishing Switzerland 2016

P.A. Ura Torres et al. (eds.), Vitamin D in Chronic Kidney Disease,

DOI 10.1007/978-3-319-32507-1_4



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76



4.1



J. Bover et al.



Introduction



Transcriptional regulation is a central process for almost all physiological eukaryotic actions. Interestingly, gene transcription is repressed in most cases since the

nuclei of eukaryotes contain a complex of genomic DNA and nucleosomes (chromatin) which occludes the binding sites of DNA-binding proteins [1, 2]. Nuclear

receptors, currently positioned at the epicenter of the “Big Bang” of molecular

endocrinology [3], are the best characterized representatives of thousands of mammalian proteins that are involved in transcriptional regulation in human tissues [2,

4]. The receptors form a superfamily, the majority of which are activated by small

lipophilic ligands [3, 5]. The subgroup of endocrine nuclear receptors bind their

specific ligands such as steroid hormones, sex and adrenal steroids, as well as thyroid hormone, retinoic acid and 1,25-dihydroxyvitamin D3 (calcitriol or

1,25(OH)2D3), among other intermediate compounds, binding and activating specific intracellular receptors. These transcription factors are now known to function

within the nucleus to regulate (enhancing or suppressing) gene expression and epigenetic changes [6]. Cloning of this nuclear receptor family of genes has contributed to the definition of new biological complexes and progressively known

pathways [6].

The human genome sequence encodes as many as 48 nuclear receptors [7, 8],

and important interrelationships between these receptors have been documented

and will be discussed in this chapter [e.g. vitamin D receptor (VDR) and retinoid X

receptor (RXR)]. On the other hand, different transcriptional effects may reside not

in the genes that are regulated, but in the overlapping but distinct ligand profile (e.g.

the VDR is structurally and functionally closely related to the pregnane X receptor

(PXR) receptor, and it does not respond to vitamin D).

The idea that vitamin D might function as a steroid-like hormone emerged in

1968 [9] and actually predated the documented discovery of 1,25(OH)2D3, the

active hormonal form of vitamin D3 [6]. The cloning in 1987 of a “binding protein”

[10] present in specific target tissues which mediates the nuclear localization of

1,25(OH)2D3 provided the final confirmation that it was indeed a steroid-like hormone capable of regulating gene expression.



4.2



Vitamin D Biology and Ubiquity of the VDR



As previously mentioned in other parts of this book, vitamin D is a prohormone that

is ultimately converted into the biologically most active vitamin D metabolite,

1,25(OH)2D3. The final step in the production of this hormonal form occurs primarily, though not exclusively, in the proximal convoluted tubular cells of the kidney

via tightly regulated 1α-hydroxylation. The cytochrome P450-containing (CYP)

enzymes responsible for catalyzing 25- and 1α-hydroxylations are the microsomal

CYP2R1 and the mitochondrial CYP27B1, respectively. 1,25(OH)2D3 circulates



4



Vitamin D Receptor and Interaction with DNA



77



bound to plasma vitamin D-binding protein (DBP) to a number of target tissues. It

has been only shown recently that the VDR present in the apical brush border of the

proximal convoluted tubular cells serves to “sense” the level of circulating

1,25(OH)2D3 [11].

The main classical actions [12] of 1,25(OH)2D3 are maintenance of proper calcium (Ca) and phosphate (P) homeostasis: the serum levels of these ions are raised

to ensure that the ion concentration is optimal for normal bone mineralization. This

is accomplished by way of direct and highly coordinated actions of the hormone on

the intestinal tract, kidney and bone and through a feedback inhibition of parathyroid hormone (PTH) production in the parathyroid glands and the induction of

fibroblast growth factor 23 (FGF23) from osteocytes of the osteoblastic lineage.

Thus, 1,25(OH)2D3 controls the expression of many genes (SPP1 or osteopontin,

TRPV6, LRP5, BGP or osteocalcin, RANKL, OPG, CYP24A1, PTH, FGF23,

PHEX and klotho, among others) associated with adequacy of bone and mineral

homeostasis [16]. 1,25(OH)2D3 also directly promotes osteoblastogenesis via

enhanced canonical Wnt signaling (LRP5) [6], prevents osteoblast apoptosis and

impacts on bone remodeling by inducing osteoblasts to terminally differentiate into

osteocytes and deposit calcified matrix [13], and promotes differentiation of precursor cells into mature osteoclasts in order to maintain an appropriate bone remodeling cycle [14, 15]. Consequently, 1,25(OH)2D3 is involved both in the formation of

osteoid matrix and in mineralization, inducing ossification in response to mechanostress/fracture (e.g. via SPP1) or supplying dietary Ca via transport to build the

mineralized skeleton (TRPV6). 1,25(OH)2D3 also regulates the production of receptor activator of nuclear factor kB ligand (RANKL) and osteoprotegerin (OPG) from

bone cells, and thus plays an important role in remodeling of normal adult bone. In

the intestinal tract and the kidney, many genes regulating Ca and P homeostasis

(CYP24A1, calbindin, TRPV6, PMCA1b, CLDN, NPT2a-c, among others) are

under the influence of 1,25(OH)2D3 [6]. By inducing TRPV6 and NPT2a-c in the

small intestine and kidney, respectively, VDR signaling favors transepithelial transport of Ca and P to generate a fully mineralized skeleton. Through the regulation of

SPP1, BGP, LRP5, RANKL, and OPG, VDR ensures the formation of high-volume

and fracture-resistant bone with connectivity that is modeled for strength via osteocyte mechano-sensing endocrine cells in the skeleton [16]. Renal megalin (a member of the low-density lipoprotein receptor superfamily that is an endocytic receptor

responsible for the renal tubular resorption of albumin and other small molecular

weight proteins) also reabsorbs the complex 25(OH)D3/DBP, and megalin is induced

by the interaction of 1,25(OH)2D3 and VDR [17].

On the other hand, VDR prevents the production of excess 1,25(OH)2D3 and

protects against ectopic calcification that is elicited by an excess of Ca or P by the

presence of feedback regulatory genes delimiting bone mineralization to the normal

skeleton, upregulating CYP24A1, inducing parathyroid calcium-sensing receptor

(CaSR), repressing PTH and PHEX, and/or inducing FGF23/klotho system [6, 18].

1,25(OH)2D3 may also directly or indirectly inhibit vascular calcification or promote osteoclast accumulation for the resorption of ectopic bone (e.g. via SPP1) [6,

19]. CYP24A1 is among the genes most strongly induced by 1,25(OH)2D3 and its



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