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5 Regulation of Vitamin D Receptor in Parathyroid Glands

5 Regulation of Vitamin D Receptor in Parathyroid Glands

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7 Vitamin D and Parathyroid Hormone Regulation in Chronic Kidney Disease



153



hypocalcemia (when VDR was already downregulated) was not able to reduce PTH

mRNA, whereas it was downregulated in rats receiving 1,25(OH)2D3 before the

initiation of hypocalcemia. These results were also confirmed in vitro by Cañadillas

et al. [31] and by Carrillo et al. [18], who observed in rat parathyroid glands that the

higher the Ca, the higher VDR expression. Thus, beside the direct posttranscriptional effect on PTH mRNA, the low Ca may also stimulate PTH levels indirectly

through lowering the parathyroid VDR expression which makes 1,25(OH)2D3 less

effective. Of note, downregulation of parathyroid VDR caused by low Ca prevents

PTH inhibition by 1,25(OH)2D3. This is an important concept in the pathogenesis of

SHPT because hypocalcemia may not allow a normal inhibition of parathyroid cells

by 1,25(OH)2D3 even when 1,25(OH)2D3 levels are normal.

Finally, Cañadillas et al. [31] characterized in vitro the signaling system responsible for the stimulation of parathyroid VDR by extracellular Ca, which takes place

through the elevation of the cytosolic Ca level, and the subsequent stimulation of the

PLA2-AA-dependent ERK1/2- pathway. High extracellular Ca also increased the

VDR promoter activity through the activation of the Sp1 transcription factor in

VDR-transfected HEKCaR cells.

Taken together, the above data support that the tight control of PTH secretion and

synthesis by Ca may in part be explained by the fact that high Ca enhances the

inhibitory action of vitamin D on parathyroid glands by augmenting VDR

expression.

Besides 1,25(OH)2D3 and Ca, several other factors have been reported to regulate

VDR expression and/or function. Calcimimetics, such as R-568 and cinacalcet HCl,

are allosteric modulators of the CaR, acting by increasing the sensitivity of the parathyroid gland to extracellular Ca. Thus, it was hypothesized that administration of

the calcimimetic R-568 may result in increased VDR expression in parathyroid tissue. In in vitro studies with whole rat parathyroid glands, the calcimimetic elicited

an increase in VDR mRNA similar to the maximum increase detected with 1.5 mM

Ca [32]. Treatment with R-568 also increased VDR protein in normal rat parathyroid glands and, interestingly, in human parathyroid glands with diffuse but not

nodular hyperplasia. These results support the convenience of using vitamin

D-calcimimetic combinations in the clinical settings. Any increase in VDR would

facilitate the inhibitory feedback of vitamin D on the parathyroid glands and would

assist in optimization of the positive action of the pharmacological administration

of 1,25(OH)2D3 or other vitamin D analogs, which in turn may reduce unwanted

side effects as high CaxP products and vascular calcifications.

It is now well-known that FGF23 decreases PTH secretion and PTH mRNA [2].

Furthermore, in normal rat parathyroid glands in vitro, addition of FGF23 to the

low-Ca medium increased parathyroid VDR and CaR mRNA and protein expression to levels similar to those observed with a high-Ca concentration [17]. The

FGF23-dependent changes in VDR and CaR expression were paralleled by the activation of the ERK1/2 activation. FGF23 also increased VDR and CaR expression

and activated ERK1/2 in the parathyroid glands of normal rats in vivo. This upregulation of CaR and VDR may represent another mechanism whereby FGF23 reduces

parathyroid function.



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M.E. Rodríguez-Ortiz et al.



In a recent study, the direct effect of Mg in the regulation of the parathyroid function was evaluated [16]; specifically, PTH secretion and the expression of the key

parathyroid cell receptors: CaR, VDR and the FGF23 receptor 1 (FGFR1)/klotho

system. The results of this study showed that parathyroid glands are sensitive to an

inhibitory effect of Mg only when a moderate low Ca concentration is present.

Furthermore, the levels of CaR, VDR, FGFR1 and klotho expression, both the

mRNA and protein, exhibited a marked increase at a Mg concentration of 2.0 mM

when compared with 0.5 mM Mg after 6-h incubation at a Ca concentration of

1.0 mM. The up-regulation of parathyroid receptors may be an additional mechanism whereby Mg inhibits parathyroid gland function. Interestingly, as deduced

from these data, Mg would favour the efficiency of therapeutic molecules targeting

the parathyroid CaR, VDR, or FGFR1/klotho.

Uremic plasma contains substances that interfere with the action of vitamin D;

preincubation of intestinal VDR with uremic ultrafiltrate significantly reduced the

interaction of the VDR-hormone complex with DNA [33]. Uremic toxins have been

shown to reduce the biological action of 1,25(OH)2D3 by suppressing receptor synthesis. In this regard, Canalejo et al. [34] addressed the role of the uremic milieu on

parathyroid VDR function by evaluating in vitro whether uremic toxins had an

effect on the regulation of parathyroid cell proliferation by 1,25(OH)2D3. While

1,25(OH)2D3 reduced the number of parathyroid cells entering the S phase of the

cell cycle, the addition of total uremic ultrafiltrate prevented this effect. Thus, to

avoid the impairment of CTR action trough the parathyroid VDR in CKD patients,

dialysis should efficiently remove VDR-targeting uremic toxins.

Figure 7.2 summarizes the signaling pathways regulating the expression of the

VDR to facilitate the inhibitory action of 1,25(OH)2D3 on parathyroid cell function.



7.6



Pathophysiology of Secondary Hyperparathyrdism



Normal kidney function is essential for mineral homeostasis. The complex mechanism regulating mineral metabolism is disrupted in CKD patients. In renal failure

patients there is an increased load of P that at very early stages of the disease stimulates FGF23 production, which in turn decreases 1,25(OH)2D3 (Fig. 7.3). Both P

overload and deficiency of 1,25(OH)2D3 enhance parathyroid gland hyperplasia

[35]. Increased levels of FGF23 and PTH help maintain the serum Ca and P within

normal levels during CKD 1–3 and even in CKD 4. High serum P concentration

directly promotes parathyroid hyperplasia and produces skeletal resistance to the

action of PTH; therefore, when P is high, more PTH is required to maintain serum

Ca concentration within the normal range. Recent studies have shown that renal

klotho expression is reduced early in the development of renal insufficiency [36].

The reduction in klotho may cause resistance to the phosphaturic action of FGF23,

and more FGF23 may be produced in an attempt to prevent the accumulation of P.

Some authors have proposed that an initial event in the development of SHPT may

be the reduction of renal klotho expression, with impairment in the ability of kidneys to excrete the excess of P.



7 Vitamin D and Parathyroid Hormone Regulation in Chronic Kidney Disease



155



Fig. 7.2 Summary of the signaling pathways involved in the regulation of vitamin D receptor

expression promoting the inhibition of parathyroid function by calcitriol



The demand for PTH increases with the progression of the renal disease. At initial stages of renal disease there is parathyroid hyperplasia with a moderate but significant reduction of CaR, VDR and FGFR1-klotho [35]. Therefore, the inhibitory

effects of Ca, vitamin D and FGF23 on parathyroid glands are impaired. The expression of these receptors is further reduced in areas of monoclonal parathyroid cell

proliferation, which is often observed in severe parathyroid hyperplasia [35, 37].

The term Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD)

includes the above described abnormalities in mineral metabolism, together with

bone disease and calcification of vessels and soft tissues.



7.7



Roles of the Calcium-Sensing Receptor and the Vitamin

D Receptor in the Pathophysiology of Secondary

Hyperparathyroidism



In order to maintain the biologic effect of 1,25(OH)2D3 on parathyroid cells, it is

necessary an adequate level of VDR, as well as of the optimal binding capacity of

the VDR to the VDRE in DNA. However, many studies have demonstrated reduced

levels of VDR in uremic parathyroid glands from SHPT patients and experimental

animals.



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M.E. Rodríguez-Ortiz et al.



Fig. 7.3 Schematic view of the pathophysiology of secondary hyperparathyroidism. GFR glomerular filtration rate, 1,25(OH)2D3 calcitriol, P phosphorus, Ca calcium, PTH parathyroid

hormone



Uremic patients develop progressive parathyroid hyperplasia as a consequence

of a maintained stimulation of parathyroid function. It is accepted that the progression of parathyroid hyperplasia is enhanced by the decrease in the serum

concentrations of 1,25(OH)2D3, the tendency to hypocalcemia and the rise in serum

P levels. However, the exact mechanisms that drive parathyroid cells to proliferate

are not clear. It is generally accepted that low 1,25(OH)2D3 contributes to the development of parathyroid hyperplasia [38]. 1,25(OH)2D3 is a primary inhibitor of parathyroid cell proliferation by acting on the gene expression of the cell cycle regulator

c-myc [39]. In vitro and in vivo studies [39–41] indicate that 1,25(OH)2D3 suppress

parathyroid hyperplasia.

During the early stages of SHPT, parathyroid growth is polyclonal, giving rise to

diffuse hyperplasia (Fig. 7.4). However, at some time point during the late stage in

the evolution of SHPT, there is a transformation from diffuse to nodular hyperplasia

as a result of monoclonal growth of parathyroid cells. Studies performed in vitro

using parathyroid tissue from uremic patients that had required parathyroidectomy

demonstrate that in nodular hyperplasia there is blunted response to the inhibitory

effect of both Ca [43] and 1,25(OH)2D3 [44]; this is explained by a reduced expression of VDR and CaR [45, 46]. Fukuda et al. [8] firstly showed a lower density of

VDR in nodular than in diffuse human parathyroid hyperplasia; similar findings were



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