Phosphorylation of Dab2 is involved in inhibited VEGF-VEGFR-2 signaling induced by downregulation of syndecan-1 in glomerular endothelial cell.

Disabled-2 (Dab2) and PAR-3 (partitioning defective 3) are reported to play critical roles in maintaining retinal microvascular endothelial cells biology by regulating VEGF-VEGFR-2 signaling. The role of Dab2 and PAR-3 in glomerular endothelial cell (GEnC) is unclear. In this study, we found that, no matter whether with vascular endothelial growth factor (VEGF) treatment or not, decreased expression of Dab2 could lead to cell apoptosis by preventing activation of VEGF-VEGFR-2 signaling in GEnC, accompanied by reduced membrane VEGFR-2 expression. And silencing of PAR-3 gene expression caused increased apoptosis of GEnC by inhibiting activation of VEGF-VEGFR-2 signaling and membrane VEGFR-2 expression. In our previous research, we found that the silencing of syndecan-1 gene expression inhibited VEGF-VEGFR-2 signaling by modulating internalization of VEGFR-2. And our further research demonstrated that downregulation of syndecan-1 lead to no significant change in the expression of Dab2 and PAR-3 both at messenger RNA and protein levels in GEnC, while phosphorylation of Dab2 was significantly increased in GEnC transfected with Dab2 small interfering RNA (siRNA) compared with control siRNA. Atypical protein kinase C (aPKC) could induce phosphorylation of Dab2, thus negatively regulating VEGF-VEGFR-2 signaling. And we found that decreased expression of syndecan-1 lead to activation of aPKC, and aPKC inhibitor treatment could block phosphorylation of Dab2 in GEnC. Besides, aPKC inhibitor treatment could activate VEGF-VGEFR-2 signaling in GEnC transfected with syndecan-1 siRNA in a dose-dependent manner. In conclusion, we speculated that phosphorylation of Dab2 is involved in preventing activation of VEGF-VEGFR-2 signaling in GEnC transfected with syndecan-1 siRNA. This provides a new target for the therapy of GEnC injury and kidney disease.

Effects of soy protein containing isoflavones in patients with chronic kidney disease: A systematic review and meta-analysis.

BACKGROUND & AIMS: Recent studies have demonstrated mixed results on the effects of soy intake in patients with CKD, and this have not been systematically analyzed. We conducted this meta-analysis to identify and evaluate the effects of soy protein intake in patients with CKD. METHODS: A comprehensive search of Medline, Embase and the Cochrane Database of Systematic Reviews was performed in December 2013 and updated in April 2014 for any new trials. Randomized trials designed to evaluate the effects of dietary soy in patients with CKD were collected. Weighted mean effect sizes were calculated for net changes using random-effect or fixed-effect model. All statistical analysis were calculated by RevMan software 5.2 available free from the Cochrane Collaboration. RESULTS: 12 studies (280 participants) were included. And we found that dietary soy was associated with significant decrease of serum creatinine, serum phosphorus, CRP (C reactive protein)and proteinuria in the predialysis subgroup. The mean difference was -0.05 mg/dL (95% CI: -0.10, -0.00 mg/dL; P = 0.04) for serum creatinine, -0.13 mg/dL (95% CI: -0.26, -0.01 mg/dL; P = 0.04) for serum phosphorus, -0.98 mg/L (95% CI: -1.25, -0.71 mg/L; P < 0.00001) for CRP, and -0.13 mg/d (95% CI: -0.18, -0.08 mg/d; P < 0.00001) for proteinuria. We did not find any significant change in serum phosphorus, CRP in the dialysis subgroup. Blood urea nitrogen (BUN) was reduced with statistical significance in the soy-treated group compared with control when the predialysis and dialysis subgroup were analyzed as a whole. The pooled estimated effects of change for BUN was -0.37 mg/dL (95% CI: -6.03, -0.11 mg/dL; P = 0.04). No significant change was detected in creatinine clearance, glomerular filtration rate, serum albumin, body weight and body mass index(BMI). CONCLUSIONS: Soy protein containing isoflavones intake significantly decreased serum creatinine, serum phosphorus, CRP and proteinura in predialysis patients, while no significant change was found in creatinine clearance and glomerular filtration rate. We also found that soy protein intake could maintain the nutritional status in dialysis patients, though no significant change in CRP, BUN, and serum phosphorus was detected. Future large, long-term RCTs are still needed to clarify the effects of soy protein intake in patients with CKD.

Downregulation of Syndecan-1 induce glomerular endothelial cell dysfunction through modulating internalization of VEGFR-2.

Ischemic acute kidney injury (AKI) remains to have high morbidity and mortality rates. The mechanism of glomerular endothelial cells (GEnC) dysfunction in the development of ischemic AKI is still unclear. Syndecan-1, one kind of heparan sulfate proteoglycan (HSPG), is extensively studied in tumor for its effects in promoting angiogenesis. In this study, we found that, Syndecan-1 was reduced in GEnC both in vivo and in vitro after hypoxia treatment. Besides, down-regulation of Syndecan-1 could lead to dysfunction and apoptosis of GEnC, as indicated by increased cell permeability, decreased cell viability and inhibited tube formation. VEGF-VEGFR-2 signaling is essential in maintaining biology of GEnC, and activation of its downstream effectors, ERK1/2, AKT, and Rac1, were inhibited in GEnC transfected with Syndecan-1 siRNA compared with control siRNA. Moreover, membrane VEGFR-2 expression was reduced significantly in GEnC transfected with Syndecan-1 siRNA. Clathrin-mediated endocytosis of VEGFR-2 is essential in the activation of VEGF-VEGFR-2 signaling. Our further study demonstrated that down-regulation of Syndecan-1 in GEnC inhibit VEGF-VEGFR-2 signaling by recruiting VEGFR-2 to the Caveolin-dependent endocytosis route, there by sequestering it from Clathrin-mediated endocytosis. Moreover, as shown by immunofluorescence and immunoprecipitation analysis, VEGFR-2 co-localizes and interacts with Syndecan-1, indicating Syndecan-1 may act as a co-receptor of VEGFR-2, thus to mediate internalization of VEGFR-2. We speculated that down-regulation of Syndecan-1 could inhibit VEGF-VEGFR-2 signaling through regulating internalization of VEGFR-2, thus leading to dysfunction and apoptosis of GEnC. This indicates a potential target for the therapy of ischemic AKI.

Down-regulation of Wt1 activates Wnt/ß-catenin signaling through modulating endocytic route of LRP6 in podocyte dysfunction in vitro.

Podocyte dysfunction plays important roles in the pathogenesis of chronic kidney disease, and Wt1 has long been considered to be a marker of podocyte, whereas its roles and mechanisms in podocyte injury are still unclear though Wt1 mutations are reported to be involved in the development of glomerular disease in human and mice. Here we show that down-regulation of Wt1 could induce podocyte dysfunction and apoptosis through activating Wnt/ß-catenin signaling. Podocytes treated with adriamycin demonstrated decreased expression of Wt1, coupled with activated Wnt/ß-catenin signaling in vitro. Reduced expression of Wt1 in podocytes transfected with Wt1 siRNA is correlated with activated Wnt/ß-catenin signaling, increased podocyte apoptosis, as well as suppressed expression of nephrin. Blockade of Wnt/ß-catenin signaling with Dickkopf-1 ameliorated podocyte injury and apoptosis induced by Wt1 siRNA. We also found that membrane LRP6 was increased dramatically in podocytes transfected with Wt1 siRNA compared with control siRNA, while no significant change was found in total LRP6. Caveolin- and clathrin-dependent endocytosis were both involved in the regulation of ß-catenin signaling. And we found that down-regulation of Wt1 in podocytes mediates activation of Wnt/ß-catenin signaling by recruiting LRP6 to the caveolin-mediated endocytosis route, thereby sequestering it from clathrin-dependent endocytosis. As a result, we concluded that Wt1 expression levels in podocytes regulate Wnt/ß-catenin signaling through modulating the endocytic fate of LRP6, and this indicates a potential target for the therapy of CKD.

Hemoglobin targets for chronic kidney disease patients with anemia: a systematic review and meta-analysis.

BACKGROUND: Numerous studies have identified a relationship between hemoglobin (Hb) levels and mortality in patients with chronic kidney disease (CKD), which have raised concerns about the optimal Hb targets in correction of anemia. Our study is designed to investigate the potential effects of targeted Hb levels, aiming to give some evidence for therapy of renal anemia. METHODOLOGY/PRINCIPAL FINDINGS: A comprehensive search of Medline, Embase and the Cochrane Database of Systematic Reviews was performed in December 2011 and updated in February 2012 for any new trials. Randomized trials designed to evaluate effects of high (generally the Hb about 13.0 g/dL) and low Hb (generally the Hb about 10.0 g/dL) targets on clinical outcomes in CKD patients with anemia were collected. All statistical analysis was calculated using the RevMan software available free from the Cochrane Collaboration. 24 trials involving 10361 patients were identified. Our findings demonstrated a statistically significant increased risk of mortality in the high Hb levels (RR 1.18; 95% CI 1.02 to 1.37) while the high and low Hb groups were both treated with ESAs. Overall, compared with low Hb levels, high Hb levels are associated with increased risk of hypertension (RR 1.40; 95% CI 1.11 to 1.75), stroke (RR 1.73; 95% CI 1.31 to 2.29), and hospitalizations (RR 1.07; 95% CI 1.01 to 1.14). However, there are no significant differences in the risk of non-fatal myocardial infarction (RR 1. 13; 95% CI 0.79 to 1.61) and renal replacement therapy (RR 1. 00; 95% CI 0.85 to 1.18). CONCLUSIONS/SIGNIFICANCES: Targeting low Hb levels are beneficial to CKD patients especially in the predialysis population. The optimal Hb targets to aim for in CKD patients and at what Hb level the risks of adverse events begin to increase remain elusive. Future studies are still needed to elucidate these questions.