Efficacy of Lanthanum Carbonate and Sevelamer Carbonate as Phosphate Binders in Chronic Kidney Disease-A Comparative Clinical Study.

(1) Background: Hyperphosphatemia is correlated with an increased rate of mortality and morbidity due to cardiovascular diseases in chronic kidney disease (CKD) patients. It can be improved by restricting dietary intake of phosphate and oral phosphate binders, such as lanthanum carbonate and sevelamer carbonate. (2) Objective: To evaluate the clinical efficacy of sevelamer carbonate in comparison to lanthanum carbonate as phosphate binders for the treatment of hyperphosphatemia in CKD patients. (3) Methods: A randomized control comparative clinical study was conducted for one year on 150 CKD patients associated with hyperphosphatemia, divided into two groups, i.e., Group 1 (n = 75) treated with sevelamer carbonate 800 mg thrice daily and Group 2 (n = 75) treated with lanthanum carbonate 500 mg thrice daily. The patients were assessed at the time of enrollment in the study, after three months and after six months from baseline for different parameters, i.e., complete blood count, liver function tests, renal function tests, electrolytes, and serum phosphate level. (4) Results: 150 CKD patients aged 51-60 participated in the study. The mean age of patients was 54 ± 4.6 years, and males (55.71%) were more common than females (44.29%). Hypertension was the common comorbidity in both groups with chronic kidney disease. After six months of treatment, the mean serum phosphate level was significantly decreased from 8.31 ± 0.09 mg/dL to 5.11 ± 0.18 (38%) in Group 1 and from 8.79 ± 0.28 mg/dl to 4.02 ± 0.12 (54%; p < 0.05) in Group 2, respectively. In both groups, no significant difference was found in other parameters such as parathyroid hormone, calcium, uric acid, LFT, RFT, CBC, etc. (5) Conclusion: Lanthanum carbonate is more efficacious in lowering serum phosphate concentrations and effectively managing hyperphosphatemia as compared to sevelamer carbonate.

Thioredoxin deficiency exacerbates vascular dysfunction during diet-induced obesity in small mesenteric artery in mice.

OBJECTIVE: Thioredoxin (Trx) is a small cellular redox protein with established antioxidant and disulfide reductase properties. We hypothesized that Trx deficiency in mice would cause increased oxidative stress with consequent redox imbalance that would exacerbate obesity-induced vascular dysfunction. METHODS: Non-transgenic (NT, C57BL/6) and dominant-negative Trx (dnTrx-Tg, low levels of redox-active protein) mice were either fed a normal diet (NC) or high fat diet plus sucrose (HFS) diet for 4 months (3-month HFD+ 1-month HFS). Weight gain, glucose tolerance test (GTT), insulin tolerance test (ITT), and other metabolic parameters were performed following NC or HFS diet. Arterial structural remodeling and functional parameters were assessed by myography. RESULTS: Our study found that dnTrx mice with lower levels of active Trx exacerbated myogenic tone, inward arterial remodeling, arterial stiffening, phenylephrine-induced contraction, and endothelial dysfunction of MA. Additionally, FeTMPyP, a peroxynitrite decomposition catalyst, acutely decreased myogenic tone and contraction and normalized endothelial function in MA from dnTrx-Tg mice on HFS via increasing nitric oxide (NO)-mediated relaxation. CONCLUSIONS: Our results indicate that deficiency of active Trx exacerbates MA contractile and relaxing properties during diet-induced obesity demonstrating that loss of redox balance in obesity is a key mechanism of vascular endothelial dysfunction.

cGMP inhibits TGF-beta signaling by sequestering Smad3 with cytosolic beta2-tubulin in pulmonary artery smooth muscle cells.

Atrial natriuretic peptide (ANP) and TGF-ß play counterregulatory roles in pulmonary vascular adaptation to chronic hypoxia. We have demonstrated that ANP-cyclic GMP (cGMP)-protein kinase G (PKG) signaling inhibits TGF-ß signaling by blocking TGF-ß-induced nuclear translocation of mothers against decapentaplegic homolog (Smad)3 in pulmonary artery smooth muscle cells (PASMC). The current study tested the novel hypothesis that activation of the ANP-cGMP-PKG pathway limits TGF-ß-induced Smad3 nuclear translocation by enhancing Smad3 binding to cytosolic anchoring proteins in isolated pulmonary artery smooth muscle cells. Cells were pretreated with vehicle or cGMP and then exposed to TGF-ß1 treatment. Cytosolic fractions were isolated and immunoprecipitated with a selective anti-Smad3 antibody. Differential proteomic analysis of the cytosolic Smad3-interacting proteins by two-dimensional differential in-gel electrophoresis and mass spectroscopy followed by coimmunoprecipitation and immunostaining demonstrated that Smad3 was bound to ß2-tubulin in a TGF-ß1/cGMP-dependent manner: binding of Smad3 to ß2-tubulin was decreased by TGF-ß1 and increased by cGMP treatment. A site-directed mutagenesis study demonstrated that mutating Smad3 at Thr388, but not Ser309, two potential sites of PKG-induced hyperphosphorylation, inhibited cGMP-induced Smad3 binding to ß2-tubulin. Further, luciferase reporter analysis showed that muation of T388 in Smad3 abolished the inhibitory effect of cGMP on TGF-ß1-induced plasminogen activator inhibitor-1 (PAI-1) transcription. In addition, disruption of ß2-tubulin with the microtubule depolymerizers nocodazole and colchicine promoted Smad3 dissociation from ß2-tubulin, increased both TGF-ß1-induced Smad3 nuclear translocation and PAI-1 mRNA expression, and abolished the inhibitory effects of cGMP on these processes. In contrast, the microtubule stabilizers paclitaxel and epothilone B increased cytosolic Smad3 binding to ß2-tubulin and enhanced the inhibitory effect of cGMP on Smad3 nuclear translocation and PAI-1 expression in response to TGF-ß1. These provocative findings suggest that sequestering Smad3 by ß2-tubulin in cytosol is a key mechanism by which ANP-cGMP-PKG signaling interferes with downstream signaling from TGF-ß and thus protects against pulmonary arterial remodeling in response to hypoxia stress.