Examinando por Autor "Deudero, Juan JP"

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Alkalinization potentiates vascular calcium deposition in an uremic milieu
(Journal of Nephrology, 2009-09-01) De solis, Alain J.; Gonzalez-Pacheco, Francisco R:; Deudero, Juan JP; Neria, Fernando; Albalate, Marta; Petkov, Vladimir; Sansibar, Luis; Fernandez-Sanchez, Ruth; Calabia, Olalla; Ortiz, Alberto; Caramelo, Carlos
Background: Vascular calcification is a serious complication of chronic kidney disease. Acid-base balance is a relevant, albeit somewhat forgotten factor in the regulation of calcium deposition. Hemodialysis patients undergo repeated episodes of alkaline loading from the dialysate, resulting in prolonged alkalinization. We have hypothesized that extracellular alkalinization may promote vascular calcification. Methods: Primary cultures of vascular smooth muscle cells were induced to calcify by the phosphate donor beta-glycerophosphate, in the presence of normal or uremic sera from hemodialysis patients and at different pH conditions. The influence of sodium bicarbonate supplementation for 2 months on aorta calcification was studied in 5/6 nephrectomized uremic rats. Results: Uremic serum increased vascular smooth muscle cell calcification (twofold over nonuremic human serum at day 12, p<0.001). Alkalinization of the extracellular medium also increased vascular smooth muscle cell calcification. Increasing the extracellular pH from 7.42 to 7.53 resulted in a 2.5-fold increase in calcium accumulation at day 12 (p<0.05). In vivo, arterial calcification was significantly higher in alkalinized uremic animals (aorta calcification index, uremic + sodium bicarbonate, 164 +/- 57 units, vs. uremic + vehicle, 56 +/- 14 units; p<0.01). Conclusions: Alkalinization increases vascular calcification in cultured cells and uremic rats. These data may be used to optimize dialysate composition and the degree of alkalinization in calcification-prone individuals with advanced renal disease.
Mechanisms of endothelial cell protection by blockade of the JAK2 pathway
(American Physiological Society, 2006-10-11) Neria, Fernando; Caramelo, Carlos; Peinado, Hector; Gónzalez-Pacheco, Francisco R.; Deudero, Juan JP; De Solis, Alain J.; Fernández-Sánchez, Ruth; Peñate, Silvia; Cano, Amparo; Castilla, M Angeles
Inhibition of the JAK2/ STAT pathway has been implicated recently in cytoprotective mech- anisms in both vascular smooth muscle cells and astrocytes. The advent of JAK2-specific inhibitors provides a practical tool for the study of this pathway in different cellular types. An interest in finding methods to improve endothelial cell (EC) resistance to injury led us to examine the effect of JAK2/STAT inhibition on EC protection. Furthermore, the signaling pathways involved in JAK2/STAT inhibi- tion-related actions were examined. Our results reveal, for the first time, that blockade of JAK2 with the tyrosine kinase inhibitor AG490 strongly protects cultured EC against cell detachment-dependent death and serum deprivation and increases reseeding efficiency. Con- firmation of the specificity of the effects of JAK2 inhibition was attained by finding protective effects on transfection with a dominant negative JAK2. Furthermore, AG490 blocked serum deprivation- induced phosphorylation of JAK2. In terms of mechanism, treatment with AG490 induces several relevant responses, both in monolayer and detached cells. These mechanisms include the following: 1) Increase and nuclear translocation of the active, dephosphorylated form of -catenin. In functional terms, this translocation is transcrip- tionally active, and its protective effect is further supported by the stimulation of EC cytoprotection by transfectionally induced excess of -catenin. 2) Increase of platelet endothelial cell adhesion molecule (PECAM)/CD31 levels. 3) Increase in total and phosphorylated AKT. 4) Increase in phosphorylated glycogen synthase kinase (GSK)3 / . The present findings imply potential practical applications of JAK2 inhibition on EC. These applications affect not only EC in the monolayer but also circulating detached cells and involve mechanistic interactions not previously described.