Uremic toxins overload accelerates renal damage in a rat model of chronic renal failure.

Uremic toxins have been suggested to promote progression of chronic renal failure by damaging tubular cells. Previous in vitro studies have indicated that some uremic toxins induce oxidative stress and activate NF-kappaB to upregulate plasminogen activator inhibitor-1 in tubular cells. These mechanisms may promote tubulointerstitial fibrosis. The present study examined whether uremic toxins induce glomerular and tubulointerstitial damage in vivo. Two uremic toxins, hippuric acid (HA) or indoleacetic acid (IAA), were tested in two independent experiments (HA-treated rats vs. non-HA-treated controls, IAA-treated rats vs. non-IAA-treated controls). The uremic toxins were administered to subtotally nephrectomized rats. Renal functions were measured periodically and glomerular sclerosis and interstitial fibrosis were examined at the end of the experimental period (18 and 24 weeks, respectively, after subtotal nephrectomy for HA and IAA treatments). Glomerular filtration rate (inulin clearance) at the end of the study period was significantly lower in uremic toxin-treated rats than in control rats (HA-treated rats: 0.090 +/- 0.004 ml/min/100 g body weight vs. non-HA-treated controls: 0.125 +/- 0.013, IAA-treated rats: 0.068 +/- 0.006 versus non-IAA-treated controls: 0.100 +/- 0.013; both p < 0.05). Beta-N-acetyl-glucoseamidase excretion was significantly higher in uremic toxin-treated rats than in control rats (HA-treated: 0.55 +/- 0.05 U/day vs. control: 0.39 +/- 0.04 at week 18, IAA-treated: 0.35 +/- 0.02 vs. control: 0.26 +/- 0.07 at week 16; both p < 0.05). Glomerular sclerosis index was significantly higher in uremic toxin-treated rats than in control rats (HA-treated: 0.85 +/- 0.16 versus control: 0.48 +/- 0.10, IAA-treated: 1.13 +/- 0.25 vs. control: 0.57 +/- 0.10; both p < 0.05). Significant enlargement of interstitial fibrosis was observed in indoleacetic acid-treated rats. These results indicate that overload of uremic toxins accelerates the loss of kidney function, glomerular sclerosis and tubulointerstitial injury in a rat model of chronic renal failure. The present study suggests the potential benefit of early intervention to remove various uremic toxins in delaying the onset of end-stage renal failure in patients with progressive renal disease.

Reassessment of ecotoxicities of 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane in Japanese quail under the OECD draft new avian one-generation reproduction test guideline.

Ecotoxicological hazards of 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (p,p'-DDT) were investigated by a one-generation reproduction study using Japanese quail (Coturnix coturnix japonica) under an Organization for Economic Co-operation and Development (OECD) draft new test guideline 206 following acute and subchronic toxicity studies. In the subchronic feeding toxicity study, tremors, convulsions, and deaths were observed with a clear sex difference, males being more susceptible than females. The estimated total number of sperm tended to decrease in a dose-dependent manner at the end of 6-week treatment. In the one-generation reproduction study conducted at dose levels of 0, 6, 30, and 150 ppm, the estimated total number of sperm tended to decrease in a dose-dependent manner with a significant difference at 150 ppm. Tremors were observed in the majority of hatchlings in the 150 ppm group and at lower incidences in the 30 ppm group. Significantly high mortality rate in chicks persisted from treatment week 3-6 in the 150 ppm group and at treatment weeks 4 and 5 in the 30 ppm group. Despite of these severe adverse effects of p,p'-DDT on hatchlings and chicks, fertilization, egg laying, eggshell thickness or embryonic development was hardly impaired by p,p'-DDT or its metabolites. From these results, it appears that the OECD draft new avian one-generation reproduction test guideline is effective for ecological hazard assessment of chemicals.

Increased Expression of the Genes for Mitotic Spindle Assembly and Chromosome Segregation in Both Lung and Pancreatic Carcinomas.

Genes whose expression was modulated in two different tumor types, lung or pancreatic carcinoma, were identified by DNA microarray and subsequent expression correlation analyses. For more accurate comparison of the gene expression between tumor and normal cells, tumor cells and normal epithelium cells were isolated by laser-captured microdissection. Genes whose expression was significantly altered in lung carcinomas or pancreatic carcinomas as compared to their normal counterparts were ranked by the T-values calculated from the Fisher's ratios and their corresponding background Fisher's ratios, followed by statistical confirmation using the Welch's t-test. Among the genes that were ranked in the top 150, either in lung carcinomas or pancreatic carcinomas, expressions of MAD2, BUB1, BUB1B, HEC, CENPE, ZWINT, KNSL1, SMC4, CCNB, TK and PMS2L6 were found to be significantly up-regulated in both tumor types. Interestingly, 8 of the above 11 genes code for the proteins involved in the mitotic spindle assembly and chromosome segregation. Furthermore, the search for genes whose expression correlated with one of the above 5 genes yielded additional genes that are also considered to be involved in mitotic spindle assembly and chromosome segregation. Thus, increased expression of the genes for mitotic spindle assembly and chromosome segregation are a common feature of at least lung carcinomas and pancreatic carcinomas and, therefore, such genes may be potential targets for widely effective anticancer agents.