An Attempt to Understand Kidney's Protein Handling Function by Comparing Plasma and Urine Proteomes

With the help of proteomics technology, the human plasma and urine proteomes, which closely represent the protein compositions of the input and output of the kidney, respectively, have been profiled in much greater detail by different research teams. Many datasets have been accumulated to form “reference profiles” of the plasma and urine proteomes. Comparing these two proteomes may help us understand the protein handling aspect of kidney function in a way, however, which has been unavailable until the recent advances in proteomics technology.After removing secreted proteins downstream of the kidney, 2611 proteins in plasma and 1522 in urine were identified with high confidence and compared based on available proteomic data to generate three subproteomes, the plasma-only subproteome, the plasma-and-urine subproteome, and the urine-only subproteome, and they correspond to three groups of proteins that are handled in three different ways by the kidney. The available experimental molecular weights of the proteins in the three subproteomes were collected and analyzed. Since the functions of the overrepresented proteins in the plasma-and-urine subproteome are probably the major functions that can be routinely regulated by excretion from the kidney in physiological conditions, Gene Ontology term enrichment in the plasma-and-urine subproteome versus the whole plasma proteome was analyzed. Protease activity, calcium and growth factor binding proteins, and coagulation and immune response-related proteins were found to be enriched.The comparison method described in this paper provides an illustration of a new approach for studying organ functions with a proteomics methodology. Because of its distinctive input (plasma) and output (urine), it is reasonable to predict that the kidney will be the first organ whose functions are further elucidated by proteomic methods in the near future. It can also be anticipated that there will be more applications for proteomics in organ function research

Occurrence of mental illness following prenatal and early childhood exposure to tetrachloroethylene (PCE)-contaminated drinking water: a retrospective cohort study

<p>Abstract</p> <p>Background</p> <p>While many studies of adults with solvent exposure have shown increased risks of anxiety and depressive disorders, there is little information on the impact of prenatal and early childhood exposure on the subsequent risk of mental illness. This retrospective cohort study examined whether early life exposure to tetrachloroethylene (PCE)-contaminated drinking water influenced the occurrence of depression, bipolar disorder, post-traumatic stress disorder, and schizophrenia among adults from Cape Cod, Massachusetts.</p> <p>Methods</p> <p>A total of 1,512 subjects born between 1969 and 1983 were studied, including 831 subjects with both prenatal and early childhood PCE exposure and 547 unexposed subjects. Participants completed questionnaires to gather information on mental illnesses, demographic and medical characteristics, other sources of solvent exposure, and residences from birth through 1990. PCE exposure originating from the vinyl-liner of water distribution pipes was assessed using water distribution system modeling software that incorporated a leaching and transport algorithm.</p> <p>Results</p> <p>No meaningful increases in risk ratios (RR) for depression were observed among subjects with prenatal and early childhood exposure (RR: 1.1, 95% CI: 0.9-1.4). However, subjects with prenatal and early childhood exposure had a 1.8-fold increased risk of bipolar disorder (N = 36 exposed cases, 95% CI: 0.9-1.4), a 1.5-fold increased risk post-traumatic stress disorder (N = 47 exposed cases, 95% CI: 0.9-2.5), and a 2.1-fold increased risk of schizophrenia (N = 3 exposed cases, 95% CI: 0.2-20.0). Further increases in the risk ratio were observed for bipolar disorder (N = 18 exposed cases, RR; 2.7, 95% CI: 1.3-5.6) and post-traumatic stress disorder (N = 18 exposed cases, RR: 1.7, 95% CI: 0.9-3.2) among subjects with the highest exposure levels.</p> <p>Conclusions</p> <p>The results of this study provide evidence against an impact of early life exposure to PCE on the risk of depression. In contrast, the results provide support for an impact of early life exposure on the risk of bipolar disorder and post-traumatic stress disorder. The number of schizophrenia cases was too small to draw reliable conclusions. These findings should be confirmed in investigations of other similarly exposed populations.</p

Long-term Effects of Commercial and Congeneric Polychlorinated Biphenyls on Ethane Production and malone Dialdehyde Levels Indicators of In-vivo lipid Peroxidation.

Ethane exhalation was increased in male Sprague-Dawley rats following a single intraperitoneal (IP) injection of Aroclor 1254 (500 mg/kg). In the first 2 weeks following Aroclor 1254 treatment, the increase in ethane exhalation was due to an inhibition of metabolism of endogenous ethane rather than to an increase in ethane production. In weeks 3 and 4 following Aroclor 1254 administration, metabolic clearance of ethane returned to and exceeded control levels, while ethane production increased to approximately twice the control rates (day 30). The HPLC determination of in situ hepatic malondialdehyde levels revealed a 2-fold increase in malondialdehyde content on day 30 following the Aroclor 1254 injection. Further, parallel increases in in situ malondialdehyde levels and ethane production rates were also found 30 days following a single IP injection of 3,3&prime;,4,4&prime;-tetrachlorobiphenyl, 2,3,4,4&prime;,5-pentachlorobiphenyl and 2,2&prime;,4,4&prime;,5,5&prime;-hexachlorobiphenyl (300 &mu;mol/kg). These effects were not reflected in increased diene conjugation. Redox state of the liver was largely unaffected, as evidenced by the relative concentrations of reduced and oxidized NADPH. However, minor changes in reduced and oxidized glutathione were noted

Signal transduction involving Ras-GTPase contributes to development of hypertension and end-organ damage in spontaneously hypertensive rats-treated with L-NAME

The purpose of this study was to examine the effect of inhibition of Ras-GTPase mediated signalling on the development of hypertension and end-organ damage in spontaneously hypertensive rats chronically treated with nitric oxide synthesis inhibitor L-NAME (SHR-L-NAME). Administration of L-NAME in drinking water (80 mg/L) for 3 weeks significantly elevated mean arterial blood pressure (MABP) (223 +/- 4 mmHg) as compared to that of SHR controls (165 +/- 3 mmHg). The administration of Ras-GTPase inhibitor FPTIII (232 ng/min) to SHR-L-NAME during the last 6 days significantly attenuated high blood pressure (192 +/- 4 mmHg). Morphological studies of the kidneys and hearts showed that treatment with FPTIII minimized the extensive arterial fibrinoid necrosis, arterial thrombosis, narrowing of arterial lumen with marked arterial hyperplastic arterial changes that were observed in vehicle treated SHR-L-NAME. L-NAME-induced increase in urine volume and protein was also significantly lower in FPTIII-treated animals. The impaired vascular responsiveness to isoprenaline in the perfused mesenteric vascular bed of SHR-L-NAME-treated animals was significantly attenuated by FPTIII treatment. In isolated per-fused hearts, recovery of left ventricular function from a 40 min of global ischemia was significantly better in FPTIII-treated SHR-L-NAME. Treatment with FPTIII also significantly reduced expression of cardiac sodium-hydrogen exchanger-1 (NHE-1) which was elevated in SHR-L-NAME. These data indicate that inhibition of Ras-GTPase-mediated signalling can attenuate end-organ damage during severe hypertension and endothelial dysfunction. (c) 2005 Elsevier Ltd. All rights reserved.The purpose of this study was to examine the effect of inhibition of Ras-GTPase mediated signalling on the development of hypertension and end-organ damage in spontaneously hypertensive rats chronically treated with nitric oxide synthesis inhibitor L-NAME (SHR-L-NAME). Administration of L-NAME in drinking water (80 mg/L) for 3 weeks significantly elevated mean arterial blood pressure (MABP) (223+/-4 mmHg) as compared to that of SHR controls (165+/-3 mmHg). The administration of Ras-GTPase inhibitor FPTIII (232 ng/min) to SHR-L-NAME during the last 6 days significantly attenuated high blood pressure (192+/-4 mmHg). Morphological studies of the kidneys and hearts showed that treatment with FPTIII minimized the extensive arterial fibrinoid necrosis, arterial thrombosis, narrowing of arterial lumen with marked arterial hyperplastic arterial changes that were observed in vehicle treated SHR-L-NAME. L-NAME-induced increase in urine volume and protein was also significantly lower in FPTIII-treated animals. The impaired vascular responsiveness to isoprenaline in the perfused mesenteric vascular bed of SHR-L-NAME-treated animals was significantly attenuated by FPTIII treatment. In isolated perfused hearts, recovery of left ventricular function from a 40 min of global ischemia was significantly better in FPTIII-treated SHR-L-NAME. Treatment with FPTIII also significantly reduced expression of cardiac sodium-hydrogen exchanger-1 (NHE-1) which was elevated in SHR-L-NAME. These data indicate that inhibition of Ras-GTPase-mediated signalling can attenuate end-organ damage during severe hypertension and endothelial dysfunction.</p