Replication of genome-wide association study identified seven susceptibility genes, affirming the effect of rs2856717 on renal function and poor outcome of IgA nephropathy.

AIM: Meta-analysis of data from a genome-wide association study (GWAS) identified seven single nucleotide polymorphisms (SNPs) as strong predictors of IgA nephropathy (IgAN). To replicate the association of these seven SNPs and understand whether they influence the clinical characteristics of IgAN, a case-control study including 521 IgAN patients and 535 controls was conducted in a Western Han cohort. METHODS: Data were analyzed using logistic regression and multifactor dimensionality reduction (MDR). Clinical data collected from 459 IgAN patients were investigated to estimate the relationship between the genotype and phenotype of IgAN. A retrospective cohort study of 315 IgAN patients was conducted to investigate the relationship between genotype and progression of renal disease over a mean period of 44.49 ± 19.94 months. RESULTS: Upon Bonferroni correction, none of the seven SNPs were associated with IgAN (corrected P-value [Pc], >0.05). A combination of the rs2856717T/C, rs9275596C/T, and rs2412971A/G had effects on the susceptibility of IgAN (P = 0.001). Marginally significant association of rs2856717 T/C recessive model for the T allele was significantly associated with estimated glomerular filtration rate (eGFR) (<60 mL/min per 1.73 m2 ) in IgAN patients (P = 0.008, Pc = 0.056, odds ratio [OR] = 1.527). The T allele at rs9275596 was significantly associated with macroscopic haematuria of IgAN patients under the dominant and additive models of inheritance, (P < 0.001, Pc = 0.007, OR = 2.983) and (P < 0.001, Pc = 0.007, OR = 2.17), respectively. Kaplan-Meier survival analysis showed that patients carrying the TT + TC genotype for rs2856717 had reduced renal survival rate than those carrying the CC genotype (85.1% vs. 92.7%, P = 0.046). CONCLUSION: rs2856717 may influence the clinical characteristics and poor outcome of IgAN. Further studies are warranted to explore the mechanisms for such genotype-disease phenotype association.

Blockade of Adenosine A2b Receptor Reduces Tumor Growth and Migration in Renal Cell Carcinoma.

Adenosine A2b receptor (A2bR) is a member of the G protein-coupled receptor superfamily members, which has been considered involved in the pathogenesis of various cancers. However, little is known about the role of A2bR renal cell carcinoma (RCC). The A2bR expression levels in RCC 769-P and Caki-1 cell lines compared with HK-2 were analyzed by qRT-PCR. 769-P and Caki-1 cells were transfected with shRNA-A2bR to knock down the expression of A2bR. Cell proliferation was detected by MTT assays and colony formation assays. Wounding healing assays and transwell assays were used to evaluate the effects of A2bR on cell capacity of invasion and migration. Finally, potential mechanisms involved in A2bR blockade's effects on altered tumor behaviors were evaluated by western blotting. We showed that A2bR were significantly up-regulated in RCC cells compared to HK-2 cell. Functionally, MRS1754, a selective A2bR antagonist, and knocking-down the expression of A2bR by shRNA reduced proliferation and migration in vitro and tumor growth in vivo. Furthermore, we demonstrated that A2bR blockade inhibited tumor progression in part via the MAPK/JNK pathway. Conclusion: Our findings suggest the A2bR potentially plays an important role in RCC progression and A2bR blockade may be a promising candidate for therapeutic intervention for renal cell carcinoma.

Higenamine alleviates cerebral ischemia-reperfusion injury in rats.

Cerebral ischemia reperfusion (I/R) injury is associated with a high incidence of neurological morbidity and mortality worldwide. Higenamine has anti-inflammatory, anti-oxidative and anti-apoptotic capacities and has been successfully used in myocardial and intestinal ischemia reperfusion. We hypothesized that higenamine might serve the same effects in cerebral I/R. In a rat model of cerebral I/R, higenamine improved functional state of nerves, significantly inhibited the I/R-induced increase in the serum level of tumor necrosis factor α (TNF-alpha) and interleukins (ILs) such as IL-1, IL-6 and IL-18, and CD14+ cells, while decreasing the axonal nerve degeneration. Together, the data demonstrate that higenamine has therapeutic effect in cerebral I/R injury.

Decreased and inactivated nuclear factor kappa B 1 (p50) in human degenerative calcified aortic valve.

BACKGROUND: Degenerative aortic valve calcification is an important factor in aortic stenosis and incompetence, but the pathogenesis is unclear. The purpose of the present study was to observe the expression of p50 in degenerative calcified aortic valves, which may provide a potential therapeutic target. METHODS: Fifteen cases of degenerative calcified aortic valve constituted the experimental group, and 10 aortic valves from patients who had undergone the Bentall operation constituted the control group. RESULTS: Immunostaining demonstrated that α-smooth muscle actin was highly expressed in valvular interstitial cells in the experimental group and that the percentage of CD68-positive cells was significantly higher in degenerative calcified aortic valves. Using bone gamma-carboxyglutamate protein as a marker of calcification showed that osteoblasts were significantly increased in the experimental valves. Western blot showed that p50 was more highly expressed and activated in the control group compared with the experimental group. Immunohistochemistry confirmed this finding and showed that p50 was principally localized to the endothelial cells of uncalcified valves, suggesting that it might play an important role in maintaining valve function. CONCLUSIONS: Inhibition of p50 activity in endothelial cells might lead to calcification in degenerative calcified aortic valves.