Sympathoexcitation by brain oxidative stress mediates arterial pressure elevation in salt-induced chronic kidney disease

Hypertension is very prevalent in chronic kidney disease and critical for its prognosis. Sympathoexcitation and oxidative stress have been demonstrated to be involved in chronic kidney disease. We have shown previously that sympathoexcitation by brain oxidative stress mediates arterial pressure elevation in the salt-sensitive hypertension model, Dahl salt-sensitive rats. Thus, we investigated whether sympathoexcitation by excessive brain oxidative stress could contribute to arterial pressure elevation in salt-induced chronic kidney disease model rats. Young (3-week-old) male Sprague-Dawley rats were randomly assigned to a uninephrectomy or sham operation and then subjected to either a normal salt (0.5%) or high-salt (8.0%) diet for 4 weeks. The young salt-loaded uninephrectomized rats exhibited sympathoexcitation, hypertension, and renal injury, proteinuria and global glomerulosclerosis together with tubulointerstitial damage. Under urethane anesthesia and artificial ventilation, renal sympathetic nerve activity, arterial pressure, and heart rate decreased to a greater degree in the salt-loaded uninephrectomized rats than in the nonsalt-loaded uninephrectomized rats and the salt-loaded or nonsalt-loaded sham-operated rats, when Tempol, a membrane-permeable superoxide dismutase mimetic, was infused acutely into the lateral cerebral ventricle. Oxidative stress in the hypothalamus, measured by lucigenin chemiluminescence, was also significantly greater. Furthermore, in the salt-loaded uninephrectomized rats, antioxidant treatment with chronic intracerebroventricular Tempol decreased sympathetic nerve activity and arterial pressure, which, in turn, led to a decrease in renal damage. Similar effects were elicited by treatment with oral moxonidine, the central sympatholytic agent. In conclusion, sympathoexcitation by brain oxidative stress may mediate arterial pressure elevation in salt-induced chronic kidney disease.     

Association of gene expression involving innate immunity and genetic variation in interleukin 28B with antiviral response

Innate immunity plays an important role in host antiviral response to hepatitis C viral (HCV) infection. Recently, single nucleotide polymorphisms (SNPs) of IL28B and host response to peginterferon α (PEG-IFNα) and ribavirin (RBV) were shown to be strongly associated. We aimed to determine the gene expression involving innate immunity in IL28B genotypes and elucidate its relation to response to antiviral treatment. We genotyped IL28B SNPs (rs8099917 and rs12979860) in 88 chronic hepatitis C patients treated with PEG-IFNα-2b/RBV and quantified expressions of viral sensors (RIG-I, MDA5, and LGP2), adaptor molecule (IPS-1), related ubiquitin E3-ligase (RNF125), modulators (ISG15 and USP18), and IL28 (IFNλ). Both IL28B SNPs were 100% identical; 54 patients possessed rs8099917 TT/rs12979860 CC (IL28B major patients) and 34 possessed rs8099917 TG/rs12979860 CT (IL28B minor patients). Hepatic expressions of viral sensors and modulators in IL28B minor patients were significantly up-regulated compared with that in IL28B major patients (≈ 3.3-fold, P < 0.001). However, expression of IPS-1 was significantly lower in IL28B minor patients (1.2-fold, P = 0.028). Expressions of viral sensors and modulators were significantly higher in nonvirological responders (NVR) than that in others despite stratification by IL28B genotype (≈ 2.6-fold, P < 0.001). Multivariate and ROC analyses indicated that higher RIG-I and ISG15 expressions and RIG-I/IPS-1 expression ratio were independent factors for NVR. IPS-1 down-regulation in IL28B minor patients was confirmed by western blotting, and the extent of IPS-1 protein cleavage was associated with the variable treatment response. CONCLUSION: Gene expression involving innate immunity is strongly associated with IL28B genotype and response to PEG-IFNα/RBV. Both IL28B minor allele and higher RIG-I and ISG15 expressions and RIG-I/IPS-1 ratio are independent factors for NVR.     

Receptor for advanced glycation end products (RAGE) is important in the prediction of recurrence in human oral squamous cell carcinoma

AIMS: Receptor for advanced glycation end products (RAGE) has recently been recognized as a cancer-associated protein responsible for cancer progression and metastasis in gastrointestinal cancers. The aim was to examine the role of RAGE in oral squamous cell carcinoma (OSCC). METHODS AND RESULTS: RAGE expression was examined by immunohistochemistry in 74 OSCC patients and evaluated with a grading based on Allred's score. RAGE expression was compared with clinicopathological parameters including clinical stage, invasive depth, nodal metastasis, disease recurrence and disease-free survival. High-grade expression of RAGE (RAGE-H) was observed in 30 (40.5%) of 74 OSCCs. RAGE-H was associated with depth of invasion (P < 0.0001) and local recurrence (P < 0.0001), but not with histological differentiation, clinical stage or nodal metastasis. Disease-free survival in patients with RAGE-H was significantly worse than in those with low-level RAGE expression. Multivariate analysis showed RAGE-H to be an independent prognostic factor for disease-free survival in OSCC patients (P = 0.0022). CONCLUSION: RAGE is a relevant factor in predicting disease recurrence and patients' prognosis in OSCC.     

Reversal of expression of 15-lipoxygenase-1 to cyclooxygenase-2 is associated with development of colonic cancer

AIMS: Two different pathways of linoleic acid (LA) metabolism have opposite effects on the development of colonic cancer: a protumoral prostaglandin cascade metabolized by cyclooxygenase (COX)-2, and an antitumoral peroxisome proliferator-activated receptor (PPAR)-gamma ligands metabolized by 15-lipooxygenase (LOX)-1. The aim was to examine the switching of the two LA metabolic pathways in colonic adenomas and carcinomas. MATERIALS AND METHODS: The expression of 15LOX-1 mRNA and COX-2 protein was examined in 54 adenomas, 21 pTis carcinoma-in-adenoma lesions and 36 pT3/p Stage II carcinomas of the colon by in-situ hybridization and immunohistochemistry, respectively. Results: 15LOX-1 expression was found in 89% (48 of 54) of adenomas, 43% (nine of 21) of adenomas and 10% (two of 21) of carcinomas in carcinoma-in-adenoma lesions, but not in pT3 carcinomas (P < 0.0001). In contrast, COX-2 production was found in 11% (six of 54) of adenomas, 52% (11 of 21) of adenomas and 71% (15 of 21) of carcinomas in carcinoma-in-adenoma lesions, and 92% (33 of 36) of pT3 carcinomas (P < 0.0001). Concurrence of 15LOX-1 down-regulation and COX-2 up-regulation was found in 6% (three of 54) of adenomas, 33% (seven of 21) of adenomas and 71% (15 of 21) of carcinomas in carcinoma-in-adenoma lesions, and 92% (33 of 36) of pT3 carcinomas (P < 0.0001). CONCLUSIONS: These results suggest that switching of LA metabolism by reversal of the expression of 15LOX-1 and COX-2 is associated with acquisition of malignant potential in colonic neoplasia.