Lanthanum prevents high phosphate-induced vascular calcification by preserving vascular smooth muscle lineage markers.

Vascular calcification (VC) represents a major cardiovascular risk factor in chronic kidney disease patients. High phosphate (Pi) levels are strongly associated with VC in this population. Therefore, Pi binders are commonly used to control high Pi levels. The aim of this work was to study the mechanism of action of lanthanum chloride (LaCl3) on the progression of Pi-induced VC through its direct effect on vascular smooth muscle cells (VSMCs) in vitro. High Pi induced VSCM Ca deposition. We evaluated the action of LaCl3, compared to gadolinium chloride (GdCl3), and found different effects on the modulation of VSMC lineage markers, such as α-actin and SM22α. In fact, only LaCl3 preserved the expression of both VSMC lineage markers compared to high Pi-treated cells. Interestingly, both LaCl3 and GdCl3 reduced the high Pi-induced elevations of bone morphogenic protein 2 mRNA expression, with no reduction of the high core binding factor-alpha 1 mRNA levels observed in calcified VSMCs. Furthermore, we also found that only LaCl3 completely prevented the matrix GLA protein mRNA levels and osteonectin protein expression elevations induced by high Pi compared to GdCl3. Finally, LaCl3, in contrast to GdCl3, prevented the high Pi-induced downregulation of Axl, a membrane tyrosine kinase receptor involved in apoptosis. Thus, our results suggest that LaCl3 prevents VC by preserving VSMC lineage markers and by decreasing high Pi-induced osteoblastic differentiation.

The combination of lanthanum chloride and the calcimimetic calindol delays the progression of vascular smooth muscle cells calcification.

Phosphate (Pi)-binders are commonly used in dialysis patients to control high Pi levels, that associated with vascular calcification (VC). The aim of this study was to investigate the effects of lanthanum chloride (LaCl(3)) on the progression of high Pi-induced VC, in rat vascular smooth muscle cells (VSMCs). Pi-induced Ca deposition was inhibited by LaCl(3), with a maximal effect at 100µM (59.0±2.5% inhibition). Furthermore, we studied the effects on VC of calcium sensing receptor (CaSR) agonists. Gadolinium chloride, neomycin, spermine, and the calcimimetic calindol significantly inhibited Pi-induced VC (55.9±2.2%, 37.3±4.7%, 30.2±5.7%, and 63.8±5.7%, respectively). To investigate the hypothesis that LaCl(3) reduces the progression of VC by interacting with the CaSR, we performed a concentration-response curve of LaCl(3) in presence of a sub-effective concentration of calindol (10nM). Interestingly, this curve was shifted to the left (IC(50) 9.6±2.6µM), compared to the curve in the presence of LaCl(3) alone (IC(50) 19.0±4.8µM). In conclusion, we demonstrated that lanthanum chloride effectively reduces the progression of high phosphate-induced vascular calcification. In addition, LaCl(3) cooperates with the calcimimetic calindol in decreasing Ca deposition in this in vitro model. These results suggest the potential role of lanthanum in the treatment of VC induced by high Pi.

Combined effects of ascorbic acid and phosphate on rat VSMC osteoblastic differentiation.

BACKGROUND: Ascorbic acid (AA) supplementation has been suggested to afford erythropoietin hyporesponsiveness and high levels of ferritin in haemodialysis (HD) patients. However, little is known about the possible side effects of this policy on vascular calcification (VC). VC, induced by a high-phosphate and uraemic milieu, is characterized by a passive deposition of calcium-phosphate (Ca-P) and an active transformation of vascular smooth muscle cells (VSMCs) in osteoblastic-like cells. The aim of these studies was to characterize the combined effects of AA and P on VC. MATERIALS AND METHODS: Rat VSMCs were challenged with inorganic P (Pi) and AA, and Ca deposition analysis was performed to quantify VC. To investigate VSMC osteoblastic differentiation, we analysed α-actin protein content and core-binding factor alpha-1 (Cbfα1/RUNX2) messenger RNA (mRNA) expression. RESULTS: When incubated with 5 mM Pi, VSMCs showed a significant increase in Ca deposition compared to control cells. Interestingly, the addition of AA in the calcification medium resulted in a dose-dependent increase in Pi-induced Ca deposition. At the same time, the combined effect of AA and Pi on VSMCs resulted in the reduction of α-actin protein content and in a 4-fold increase of Cbfα1/RUNX2 mRNA expression. CONCLUSIONS: We demonstrated that AA combined with Pi increases Ca deposition in rat VSMCs. The role of AA as cofactor in osteoblastic differentiation was demonstrated by phenotypic changes in VSMCs and enhanced bone mineralization key gene expression. These in vitro preliminary data suggest a potential role for AA combined with Pi in worsening VC.

The calcimimetic calindol prevents high phosphate-induced vascular calcification by upregulating matrix GLA protein.

BACKGROUND: High serum phosphate (Pi) levels represent a major issue in dialysis patients, because associate with secondary hyperparathyroidism, vascular calcification (VC), and cardiovascular outcomes. In this population, calcimimetics are used to control secondary hyperparathyroidism, hyperphosphatemia, and, more recently, to delay the progression of VC. The aim of this in vitro study was to investigate the direct effects of the calcimimetic calindol on the progression of high Pi-induced VC. METHODS: Rat vascular smooth muscle cells (VSMCs) were incubated with high Pi concentrations, and the effects of calindol were investigated on vascular calcium deposition and VSMC osteoblastic differentiation. RESULTS: Calindol inhibited calcium deposition concentration-dependently with a maximal inhibition of 64.0 ± 5.2% achieved at 100 nM. Furthermore, calindol was able to partially prevent the high Pi-induced bone morphogenic protein 2 (BMP-2) expression upregulation (32.4 ± 4.6% of inhibition; p < 0.01). Interestingly, the pretreatment with calindol enhanced the matrix Gla protein (MGP) gene expression significantly, compared to high Pi-treated cells (40.2 ± 6.6% of increase, p < 0.01). CONCLUSIONS: In conclusion, we demonstrated that the calcimimetic calindol prevents high Pi-induced VC by affecting osteoblastic differentiation in vitro. In particular, the inhibitory effect of calindol on VC is probably due to its stimulatory role on the calcium-sensing receptor, leading to an increase in the synthesis of MGP by VSMCs.

[Cardioprotective effect of vitamin D in nondialyzed patients with stage 3-5 CKD]. / Effetti cardioprotettivi della vitamina D nei pazienti con malattia renale cronica allo stadio 3-5 non in dialisi.

Epidemiological and observational data indicate that there is a close relationship between progressive renal dysfunction in chronic kidney disease (CKD), cardiovascular disease, and mortality. In addition, deficits in vitamin D (25-hydroxyvitamin D) and vitamin D receptor (VDR) activation play a crucial role in adversely affecting cardiovascular health in CKD patients. Even in patients with mild CKD, renal dysfunction is associated with cardiovascular events. Modulation of vitamin D levels results in correlative regulatory effects on mineral homeostasis, hypertension, and vascular calcification. The use of VDR activators such as paricalcitol to treat these and other parameters outside of cardiovascular and renal disease not only results in enhanced patient health but significantly reduces the mortality risk in CKD patients.

Management of secondary hyperparathyroidism in the elderly patient with chronic kidney disease.

Patients with chronic kidney disease (CKD) are generally affected by secondary hyperparathyroidism (SHPT). High phosphate, low calcium and vitamin D deficiency represent the classical 'triad' involved into the pathogenesis of SHPT in renal insufficiency, in which downregulation of the parathyroid vitamin D receptor and calcium-sensing receptor represents a critical step. Recently, new studies indicate that fibroblast growth factor 23 may play a central role in the regulation of phosphate-vitamin D metabolism in patients with CKD. These new insights into the pathogenesis of SHPT will possibly improve the treatment of this condition in patients with CKD. The 'modern' treatment of SHPT in CKD patients consists of free-calcium and aluminium phosphate binders, vitamin D receptor activators and calcimimetics. However, calcium- and aluminium-based phosphate binders and calcitriol are therapeutic tools that are not without complications, including increasing the risk of cardiovascular calcification in patients with CKD. This review summarizes the current understanding and evidence supporting strategies for SHPT treatment in CKD patients, with particular focus on the elderly, although specific guidelines for control of this disorder in this age group are lacking.

Pathophysiology of calcium and phosphate metabolism impairment in chronic kidney disease.

Secondary hyperparathyroidism (SHPT) is a classical feature of chronic kidney disease (CKD). Commonly, hypocalcemia, hyperphosphatemia, and vitamin D deficiency are involved into the pathogenesis of SHPT. Parathyroid (PT) glands are characterized by a low turnover and rarely undergo mitoses. However, in the presence of low calcium, high phosphorus, vitamin D deficiency, and uremia, PT cells leave quiescence. In the last decade, both new molecular and cellular mechanisms have been investigated in the pathophysiology of SHPT, between them the emerging role of the PT vitamin D receptor and calcium-sensing receptor. Furthermore, recent studies indicate that the fibroblast growth factor-23 may play a central role in the regulation of phosphate-vitamin D metabolism in CKD. Certainly, in the next future, these new insights into the pathogenesis of SHPT will give the possibility to improve the treatment of this condition in the CKD population.

A cross-cultural study of the psychometric properties of the Reactive-Proactive Aggression Questionnaire among Italian nonclinical adolescents.

Five independent studies were used to test the hypothesis that a reliable 2-factor structure underlies the Reactive-Proactive Aggression Questionnaire (RPQ) items and that the 2 scales show distinct patterns of association with personality and bullying behavior measures. Study 1 (N = 1,447) gave evidence of a clear 2-factor structure of RPQ items with factor loading matrices closely matching reactive (congruence coefficient = .90) and proactive (congruence coefficient = .91) models of item assignment. The RPQ 2-factor structure was consistently replicated in Study 2 (N = 662), as well as across the remaining 3 studies. In Study 3 (N = 536), Neuroticism differentiated reactive and proactive forms of aggression. In Study 4 (N = 674), self-reports of bullying behaviors were selectively correlated with proactive aggression. Findings confirm and extend the differential correlates of proactive-reactive aggression and also support the psychometric properties of the RPQ in a different cultural context. Finally, in Study 5 (N = 347), the RPQ scales showed adequate 2-month test-retest reliability. (PsycINFO Database Record (c) 2009 APA, all rights reserved).

Restoring the physiology of vitamin D receptor activation and the concept of selectivity.

Abnormalities of bone mineral parameters (calcium, phosphate, vitamin D, and parathyroid hormone) are nearly always present in patients with chronic kidney disease (CKD). These typically consist of hypocalcemia, hyperphosphatemia, abnormalities of vitamin D metabolism, and secondary hyperparathyroidism, and are now defined as CKD mineral bone disorders (CKD-MBD). Currently, emerging evidence indicates that deficiencies in vitamin D receptor (VDR) activation play crucial roles in adversely affecting the cardiovascular health of CKD patients. VDRs are not restricted to skeletal tissue, but are instead widely expressed throughout the body at several sites, such as in cardiac tissue, vascular smooth muscle cells, endothelial cells, renal tissue, and cells of the immune system. Restoring the physiology and modulation of VDR activator levels results in correlative regulatory effects on mineral homeostasis, hypertension, cardiovascular disease, and vascular calcification, as well as a number of other endpoints in cardiac and renal pathology. Among the compounds available for treatment of CKD-MBD, paricalcitol is a selective VDR activator. The term 'selective' refers to paricalcitol being more selective in affecting VDR pathways in the parathyroid gland compared with bone and intestine. As such, paricalcitol's selectivity allows for a wider therapeutic window with effects beyond parathyroid hormone control and mineral management, and may explain, in part, the increased survival advantage with paricalcitol treatment.

Vascular calcification in chronic kidney disease: a changing scenario.

Vascular calcification (VC) is one of the most dramatic consequences of chronic kidney disease (CKD). It has been considered a passive process, resulting essentially from mineral metabolism disorders and alterations in calcium and phosphate balance. But during the last decade, it has been elucidated how VC is not only a passive but more properly an active process, in which different factors are deeply involved. The progression of vessel wall mineralization is commonly associated with factors that promote VC, such as age, dialysis vintage and mineral metabolism abnormalities. Furthermore, many substances seem to be dynamically implicated in the regulation of the molecular mechanisms of VC. Between them, the matrix Gla protein and fetuin-A have recently been investigated in CKD. In this review, along with the most promising possible treatments, the new molecular mechanisms involved in the VC process will be elucidated.

The Effect of Paricalcitol on Vascular Calcification and Cardiovascular Disease in Uremia: Beyond PTH Control.

Secondary hyperparathyroidism is a systemic disorder that associates with bone and cardiovascular disease, including arterial calcification. Treatment with calcitriol, the active form of vitamin D, reduces parathyroid hormone levels, but may result in elevations in serum calcium and phosphorus, increasing the risk of vascular calcification in dialysis patients. New vitamin D receptor activators (VDRAs) have been developed and investigated with the rationale to treat high serum PTH levels, with a reduced risk of hypercalcemia and hyperphosphatemia. Paricalcitol is a selective VDRA that suppresses PTH secretion with minimal increases on serum calcium and phosphate. Moreover, paricalcitol prevents vascular calcification in experimental models of renal failure, compared with calcitriol.

Importance of vitamin D receptor activation in clinical practice.

Continuously emerging evidence indicates that defi ciencies in 25-hydroxyvitamin D and consequently vitamin D receptor (VDR) activation play crucial roles in adversely affecting cardiovascular (CV) health in the general population and those at high risk of CV disease, as well as in patients with chronic kidney disease (CKD). In CKD patients, a lack of VDR activation is one of the main pathophysiological factors contributing to secondary hyperparathyroidism (SHPT). However, this lack of VDR activation has numerous additional implications on CV and renal function, with SHPT being only one symptom of a much more extensive disorder. VDRs are widely expressed throughout the body with manifold activities that involve feedback loops within the CV, immune, and renal systems. Modulation of VDR activator levels results in correlative regulatory effects on mineral homeostasis, hypertension, vascular disease, and vascular calcifi cation, as well as a number of other endpoints in cardiac and renal pathology. Among compounds available for the treatment of SHPT, paricalcitol is a selective VDR activator. The term 'selective' refers to paricalcitol being more selective in affecting VDR pathways in the PTH gland compared with bone and intestine. As such, paricalcitol's selectivity allows for a wider therapeutic window with effects beyond PTH control and mineral management, and may explain, in part, the increased survival advantage with paricalcitol treatment.