Effect of Uric Acid on the Development of Chronic Kidney Disease: The Korean Multi-Rural Communities Cohort Study / 예방의학회지

OBJECTIVES: Several studies have investigated the effects of serum uric acid (SUA) levels on chronic kidney disease (CKD), with discrepant results. The effect of SUA levels on CKD development was studied in the Korean rural population. METHODS: A total of 9695 participants aged ≥40 years were recruited from 3 rural communities in Korea between 2005 and 2009. Of those participants, 5577 who participated in the follow-up and did not have cerebrovascular disease, myocardial infarction, cancer, or CKD at baseline were studied. The participants, of whom 2133 were men and 3444 were women, were grouped into 5 categories according to their quintile of SUA levels. An estimated glomerular filtration rate of < 60 mL/min/1.73 m2 at the time of follow-up was considered to indicate newly developed CKD. The effects of SUA levels on CKD development after adjusting for potential confounders were assessed using Cox proportional hazard models. RESULTS: Among the 5577 participants, 9.4 and 11.0% of men and women developed CKD. The hazard ratio (HR) of CKD was higher in the highest quintile of SUA levels than in the third quintile in men (adjusted HR, 1.60; 95% confidence interval [CI], 1.02 to 2.51) and women (adjusted HR, 1.56; 95% CI, 1.14 to 2.15). Furthermore, CKD development was also more common in the lowest quintile of SUA levels than in the third quintile in men (adjusted HR, 1.83; 95% CI, 1.15 to 2.90). The effect of SUA was consistent in younger, obese, and hypertensive men. CONCLUSIONS: Both high and low SUA levels were risk factors for CKD development in rural Korean men, while only high levels were a risk factor in their women counterparts.

Association between Interferon-Inducible Protein 6 (IFI6) Polymorphisms and Hepatitis B Virus Clearance

CD8+ T cells are key factors mediating hepatitis B virus (HBV) clearance. However, these cells are killed through HBV-induced apoptosis during the antigen-presenting period in HBV-induced chronic liver disease (CLD) patients. Interferon-inducible protein 6 (IFI6) delays type I interferon-induced apoptosis in cells. We hypothesized that single nucleotide polymorphisms (SNPs) in the IFI6 could affect the chronicity of CLD. The present study included a discovery stage, in which 195 CLD patients, including chronic hepatitis B (HEP) and cirrhosis patients and 107 spontaneous recovery (SR) controls, were analyzed. The genotype distributions of rs2808426 (C > T) and rs10902662 (C > T) were significantly different between the SR and HEP groups (odds ratio [OR], 6.60; 95% confidence interval [CI], 1.64 to 26.52, p = 0.008 for both SNPs) and between the SR and CLD groups (OR, 4.38; 95% CI, 1.25 to 15.26; p = 0.021 and OR, 4.12; 95% CI, 1.18 to 14.44; p = 0.027, respectively). The distribution of diplotypes that contained these SNPs was significantly different between the SR and HEP groups (OR, 6.58; 95% CI, 1.63 to 25.59; p = 0.008 and OR, 0.15; 95% CI, 0.04 to 0.61; p = 0.008, respectively) and between the SR and CLD groups (OR, 4.38; 95% CI, 1.25 to 15.26; p = 0.021 and OR, 4.12; 95% CI, 1.18 to 14.44; p = 0.027, respectively). We were unable to replicate the association shown by secondary enrolled samples. A large-scale validation study should be performed to confirm the association between IFI6 and HBV clearance.

Induction of Inducible Nitric Oxide Synthase Expression by Manganese in C6 Glioma Cells / 대한산업의학회지

OBJECTIVE: It is well established that manganese neurotoxicity is associated with clinical symptoms similar to those of idiopathic Parkinson's disease. Recent research has shown that the exposure to manganese (MnCl2) leads to induction of iNOS in BV2 microglial cells via iNOS transcriptional up-regulation and activation of both MAPKs and PI3K/Akt signaling pathways. Here, we further investigated the effect and the action mechanism of MnCl2 on iNOS expression in C6 glioma cells. METHODS: Western blot analyses demonstrated that treatment with MnCl2 at 250 micronmeter was sufficient to induce iNOS at both the protein and mRNA levels in C6 cells. RESULTS: These studies demonstrated that the induction of iNOS protein and mRNA was visible after 4h- and 2 h-treatment with MnCl2, respectively. MnCl2 treatment led to strong phosphorylation of JNKs and ERKs, members of MAP kinases (MAPKs), and Akt, a PI3-kinase (PI3K) downstream effector, in C6 cells. MnCl2 treatment had no effect on I kappa B-alpha in C6 cells. Notably, pretreatment with LY294002 (a PI3K inhibitor), which inhibited phosphorylation of Akt by MnCl2, caused strong suppression of MnCl2- induced iNOS protein and mRNA expression in C6 cells. Moreover, pretreatment with SP600125 (an inhibitor of JNKs) and PD98050 (an inhibitor of ERKs), which respectively interfered with MnCl2-mediated phosphorylation of JNKs and ERKs, led to the partial suppression of MnCl2-induced iNOS protein. Interestingly, pretreatment with LY294002 inhibited phosphorylation of not only Akt, but also ERKs and JNKs, in response to MnCl2. Moreover, there was an effective suppression of MnCl2-mediated phosphorylation of AKT by SP600125. CONCLUSION: These results collectively suggest that MnCl2 induces iNOS expression in C6 glioma cells via activation of PI3K/Akt and JNK-ERK MAPK signaling proteins, whose activations seem to be mutually interconnected in response to MnCl2.