Calcitriol and calcimimetics are used to treat hyperparathyroidism secondary to chronic kidney disease (CKD). Calcitriol administration and the subsequent increase in serum calcium concentration ...decrease parathyroid hormone (PTH) levels, which should reduce bone remodeling. We have previously reported that, when maintaining a given concentration of PTH, the addition of calcimimetics is associated with an increased bone cell activity. Whether calcitriol administration affects bone cell activity while PTH is maintained constant should be evaluated in an animal model of renal osteodystrophy. The aim of the present study was to compare in CKD PTH‐clamped rats the bone effects of calcitriol and calcimimetic administration. The results show that the administration of calcitriol and calcimimetic at doses that induced a similar reduction in PTH secretion produced dissimilar effects on osteoblast activity in 5/6 nephrectomized (Nx) rats with secondary hyperparathyroidism and in Nx rats with clamped PTH. Remarkably, in both rat models, the administration of calcitriol decreased osteoblastic activity, whereas calcimimetic increased bone cell activity. In vitro, calcitriol supplementation inhibited nuclear translocation of β‐catenin and reduced proliferation, osteogenesis, and mineralization in mesenchymal stem cells differentiated into osteoblasts. In conclusion, besides the action of calcitriol and calcimimetics at parathyroid level, these treatments have specific effects on bone cells that are independent of the PTH level.
In vivo studies used 5/6 nephrectomy with parathyroidectomy and replacement of exogenous PTH to eliminate the osteogenic effect of PTH comparing the bone effects of calcitriol vs calcimimetic. The osteogenesis of mesenchymal stem cells in presence of calcitriol was also evaluated. Results show calcimimetic increases bone formation, while calcitriol reduces it. In vitro, calcitriol presence reduces mineralization and osteogenesis of stem cells into osteoblasts. In this experimental study and independently of PTH, we demonstrate that calcitriol administration reduces bone formation.
RA patients are at higher risk of cardiovascular disease, influenced by therapies. Studying their cardiovascular and cardiometabolic proteome can unveil biomarkers and insights into related ...biological pathways.
This study included two cohorts of RA patients: newly diagnosed individuals (n=25) and those with established RA (disease duration >25 years, n=25). Both cohorts were age and sex-matched with a control group (n=25). Additionally, a longitudinal investigation was conducted on a cohort of 25 RA patients treated with methotrexate and another cohort of 25 RA patients treated with tofacitinib for 6 months. Clinical and analytical variables were recorded, and serum profiling of 184 proteins was performed using the Olink technology platform.
RA patients exhibited elevated levels of 75 proteins that might be associated with cardiovascular disease. In addition, 24 proteins were increased in RA patients with established disease. Twenty proteins were commonly altered in both cohorts of RA patients. Among these, elevated levels of CTSL1, SORT1, SAA4, TNFRSF10A, ST6GAL1 and CCL18 discriminated RA patients and HDs with high specificity and sensitivity. Methotrexate treatment significantly reduced the levels of 13 proteins, while tofacitinib therapy modulated the expression of 10 proteins. These reductions were associated with a decrease in DAS28. Baseline levels of SAA4 and high levels of BNP were associated to the non-response to methotrexate. Changes in IL6 levels were specifically linked to the response to methotrexate. Regarding tofacitinib, differences in baseline levels of LOX1 and CNDP1 were noted between non-responder and responder RA patients. In addition, response to tofacitinib correlated with changes in SAA4 and TIMD4 levels.
In summary, this study pinpoints molecular changes linked to cardiovascular disease in RA and proposes candidate protein biomarkers for distinguishing RA patients from healthy individuals. It also highlights how methotrexate and tofacitinib impact these proteins, with distinct alterations corresponding to each drug's response, identifying potential candidates, as SAA4, for the response to these therapies.
Chronic kidney disease (CKD) is one of the fastest growing causes of death worldwide, emphasizing the need to develop novel therapeutic approaches. CKD predisposes to acute kidney injury (AKI) and ...AKI favors CKD progression. Mitochondrial derangements are common features of both AKI and CKD and mitochondria-targeting therapies are under study as nephroprotective agents. PGC-1α is a master regulator of mitochondrial biogenesis and an attractive therapeutic target. Low PGC-1α levels and decreased transcription of its gene targets have been observed in both preclinical AKI (nephrotoxic, endotoxemia, and ischemia-reperfusion) and in experimental and human CKD, most notably diabetic nephropathy. In mice, PGC-1α deficiency was associated with subclinical CKD and predisposition to AKI while PGC-1α overexpression in tubular cells protected from AKI of diverse causes. Several therapeutic strategies may increase kidney PGC-1α activity and have been successfully tested in animal models. These include AMP-activated protein kinase (AMPK) activators, phosphodiesterase (PDE) inhibitors, and anti-TWEAK antibodies. In conclusion, low PGC-1α activity appears to be a common feature of AKI and CKD and recent characterization of nephroprotective approaches that increase PGC-1α activity may pave the way for nephroprotective strategies potentially effective in both AKI and CKD.
FGF23 Fails to Inhibit Uremic Parathyroid Glands CANALEJO, Rocío; CANALEJO, Antonio; MARTINEZ-MORENO, Julio Manuel ...
Journal of the American Society of Nephrology,
07/2010, Letnik:
21, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Fibroblast growth factor 23 (FGF23) modulates mineral metabolism by promoting phosphaturia and decreasing the production of 1,25-dihydroxyvitamin D(3). FGF23 decreases parathyroid hormone (PTH) mRNA ...and secretion, but despite a marked elevation in FGF23 in uremia, PTH production increases. Here, we investigated the effect of FGF23 on parathyroid function in normal and uremic hyperplastic parathyroid glands in rats. In normal parathyroid glands, FGF23 decreased PTH production, increased expression of both the parathyroid calcium-sensing receptor and the vitamin D receptor, and reduced cell proliferation. Furthermore, FGF23 induced phosphorylation of extracellular signal-regulated kinase 1/2, which mediates the action of FGF23. In contrast, in hyperplastic parathyroid glands, FGF23 did not reduce PTH production, did not affect expression of the calcium-sensing receptor or vitamin D receptor, and did not affect cell proliferation. In addition, FGF23 failed to activate the extracellular signal-regulated kinase 1/2-mitogen-activated protein kinase pathway in hyperplastic parathyroid glands. We observed very low expression of the FGF23 receptor 1 and the co-receptor Klotho in uremic hyperplastic parathyroid glands, which may explain the lack of response to FGF23 in this tissue. In conclusion, in hyperparathyroidism secondary to renal failure, the parathyroid cells resist the inhibitory effects of FGF23, perhaps as a result of the low expression of FGF23 receptor 1 and Klotho in this condition.
Background
Vascular calcification (VC) is highly prevalent in patients with chronic kidney disease (CKD). Low magnesium levels are associated with VC, and recent in vitro studies confirm a protective ...role of magnesium, which is mediated by its entry into the VSMCs through the Transient Receptor Potential Melastatin 7 (TRPM7) channel. The role of Angiotensin II (Ang II) on VC is still unclear. As Ang II is able to stimulate TRPM7 activity, we hypothesize that it might prevent VC. Thus, the aim of this study was to dissect the direct effect of Ang II on VC.
Materials and methods
We worked with a model of high phosphate (HP)‐induced calcification in human aortic smooth muscle cells, which resembles the CKD‐related VC.
Results
Addition of Ang II to cells growing in HP decreased calcification, which was associated with the upregulation of the osteogenic factors BMP2, Runx2/Cbfa1, Osterix and ALP. A reduction of magnesium entry into the HP‐calcifying cells was found. The treatment with Ang II avoided this reduction, which was reversed by the cotreatment with the TRPM7‐inhibitor 2‐APB. The protective effect of Ang II was related to AT1R‐induced ERK1/2 MAPKinase activation. HP‐induced calcification was also associated with the upregulation of the canonical Wnt/beta‐catenin pathway, while its downregulation was related to attenuation of calcification by Ang II.
Conclusion
As hypothesized, Ang II prevented phosphate‐induced calcification in VSMCs, which appears mediated by the increase of magnesium influx and by the activation of the ERK1/2 and the inhibition of the canonical Wnt/beta‐catenin signalling pathways.
Wnt/β-catenin pathway controls biochemical processes related to cell differentiation. In committed cells the alteration of this pathway has been associated with tumors as hepatocellular carcinoma or ...hepatoblastoma. The present study evaluated the role of Wnt/β-catenin activation during human mesenchymal stem cells differentiation into hepatocytes. The differentiation to hepatocytes was achieved by the addition of two different conditioned media. In one of them, β-catenin nuclear translocation, up-regulation of genes related to the Wnt/β-catenin pathway, such as Lrp5 and Fzd3, as well as the oncogenes c-myc and p53 were observed. While in the other protocol there was a Wnt/β-catenin inactivation. Hepatocytes with nuclear translocation of β-catenin also had abnormal cellular proliferation, and expressed membrane proteins involved in hepatocellular carcinoma, metastatic behavior and cancer stem cells. Further, these cells had also increased auto-renewal capability as shown in spheroids formation assay. Comparison of both differentiation protocols by 2D-DIGE proteomic analysis revealed differential expression of 11 proteins with altered expression in hepatocellular carcinoma. Cathepsin B and D, adenine phosphoribosyltransferase, triosephosphate isomerase, inorganic pyrophosphatase, peptidyl-prolyl cis-trans isomerase A or lactate dehydrogenase β-chain were up-regulated only with the protocol associated with Wnt signaling activation while other proteins involved in tumor suppression, such as transgelin or tropomyosin β-chain were down-regulated in this protocol. In conclusion, our results suggest that activation of the Wnt/β-catenin pathway during human mesenchymal stem cells differentiation into hepatocytes is associated with a tumoral phenotype.
We have previously demonstrated that the activation of rat parathyroid calcium-sensing receptor (CaSR) upregulates VDR expression in vivo (Garfia B, Cañadillas S, Luque F, Siendones E, Quesada M, ...Almadén Y, Aguilera-Tejero E, Rodríguez M. J Am Soc Nephrol 13: 2945-2952, 2002; Rodriguez ME, Almaden Y, Cañadillas S, Canalejo A, Siendones E, Lopez I, Aguilera-Tejero E, Martin D, Rodriguez M. Am J Physiol Renal Physiol 292: F1390-F1395, 2007). The present study was designed to characterize the signaling system that mediates the stimulation of parathyroid VDR gene expression by extracellular calcium. Experiments were performed in vitro by the incubation of rat parathyroid glands and in vivo with normal and uremic (Nx) rats receiving injections of CaCl(2) or EDTA to obtain hypercalcemic or hypocalcemic clamps. A high calcium concentration increased VDR expression. The addition of arachidonic acid (AA) to the low-calcium medium produced an increase in VDR mRNA of the same magnitude as that observed with high calcium. The addition of ionophore to the low-calcium medium also increased VDR mRNA expression. High calcium or the addition of AA to the low-calcium medium induced the activation (phosphorylation) of ERK1/2-MAPK. The specific inhibition of the ERK1/2-MAPK activity prevented the stimulation of VDR expression by high calcium or AA. These results suggest that AA regulates parathyroid VDR gene expression through the activation of the ERK1/2-MAPK. CaSR activation induced the activation of transcription factor Sp1, but not of NF-κB p50 or p65 or activator protein-1. The addition of AA to the low-calcium medium increased specific DNA-binding activity of Sp1 to almost the same level as high calcium, which was prevented by the inhibition of ERK1/2. Furthermore, mithramycin A (a Sp1 inhibitor) prevented the upregulation of VDR mRNA by high calcium. Finally, both sham and Nx hypercalcemic rats showed similar increased levels of VDR mRNA compared with sham and Nx hypocalcemic rats. Our results demonstrate that extracellular calcium stimulates VDR expression in parathyroid glands through the elevation of the cytosolic calcium level and the stimulation of the PLA(2)-AA-dependent ERK1/2-pathway. Furthermore, the transcription factor Sp1 mediates this effect.
Vascular calcification is common in patients with chronic kidney disease (CKD) and contributes to the increased rate of cardiovascular morbidity and mortality. The mechanisms regulating vascular ...calcification are under investigation; it is accepted that vascular calcification is an active and complex process involving many factors that promote or inhibit calcification. Vascular smooth muscle cells undergo transformation into osteogenic cells. This transformation is being stimulated by high phosphate, and more recently the role of the calcium phosphate nanocrystals has gained attention. Experimental models of uremia and in vitro studies have shown that an excess of calcitriol accelerates vascular calcification. However, observational studies suggest that vitamin D provides a survival advantage for patients with CKD. Experimental work shows that for similar serum concentrations of calcium and phosphate paricalcitol produces less vascular calcification than calcitriol suggesting a differential effect at the cellular level. Important issues regarding the role of vitamin D compounds on vascular calcification will be commented in this review.
The progression of chronic kidney disease (CKD) involves the development of alterations in mineral metabolism that are closely related to cardiovascular outcomes and bone disease. Hypomagnesemia is ...associated with more rapid progression of CKD and other comorbidities. Our objective was to analyze in CKD patients stages 3–4 the impact of the administration of magnesium (Mg) carbonate on bone mineral density (BMD) and hemodynamic changes associated with by vascular calcification (VC).
Patients with CKD stages 3–4 were randomized into controls (n=12) or intervention (n=7) group receiving 360mg of Mg carbonate daily during a 15-month period. Parameters related to mineral metabolism, BMD, VC, and pulse wave velocity (PWV) were evaluated.
Supplementation with Mg produced an increase in the urinary excretion of Mg while serum Mg levels remained stable and no episodes of hypermagnesemia were reported. In addition, no significant changes were found in the degree of VC assessed by Adragao index, however, both serum and urine Mg were significantly associated with a decrease in PWV, suggesting an increase in vascular compliance. Likewise, BMD did not change following treatment, but serum Mg significantly correlated with the levels of N-terminal propeptide of collagen alpha-1(I) chain (PINP), a marker of bone synthesis.
In sum, these results suggest a possible beneficial effect of Mg on vascular compliance with no detrimental effects on bone status. In addition, our results highlight the need to consider monitorization of urinary Mg status in CKD patients.
La progresión de la enfermedad renal crónica (ERC) supone el desarrollo de alteraciones del metabolismo mineral que están estrechamente relacionadas con eventos cardiovasculares y enfermedad ósea. La hipomagnesemia se asocia con una progresión más rápida de la ERC, así como con otras comorbilidades. Nuestro objetivo fue analizar en pacientes con ERC estadios 3-4 el impacto de la administración de carbonato de magnesio (Mg) sobre la densidad mineral ósea (DMO) y los cambios hemodinámicos asociados a la calcificación vascular (CV).
Los pacientes con enfermedad renal crónica estadios 3-4 se distribuyeron aleatoriamente en los grupos control (n=12) o intervención (n=7), que recibió 360 mg de carbonato de Mg diariamente durante un periodo de 15 meses. Se evaluaron parámetros relacionados con el metabolismo mineral además de la DMO, CV, y velocidad de onda de pulso (VOP).
La suplementación con Mg produjo un aumento en la excreción urinaria de Mg, mientras que los niveles séricos de Mg permanecieron estables y no se reportaron episodios de hipermagnesemia. Además, no se observaron cambios significativos en cuanto al grado de CV valorado en base al índice de Adragao. No obstante, tanto los niveles séricos como urinarios de Mg se asociaron significativamente con un descenso en la VOP, lo que sugiere un aumento en la distensibilidad vascular. De manera similar, la DMO no se modificó con la administración del tratamiento, pero los niveles séricos de Mg correlacionaron significativamente con los del propétido N-terminal del colágeno tipo I (PINP), un marcador de la síntesis ósea.
En conjunto, estos resultados sugieren un posible efecto beneficioso del Mg sobre la distensibilidad vascular sin efectos negativos a nivel óseo. Además, nuestros resultados subrayan la necesidad de considerar la monitorización del nivel de Mg urinario en pacientes con ERC.
PDF
