No abstract

Schizophrenia is thought to be a multifactorial disease with complex mode of inheritance. Using a two-stage strategy for another complex disorder, a number of putative IDDM-susceptibility genes have recently been mapped. We now report the results of a two-stage genome-wide search for genes conferring susceptibility to schizophrenia. In stage I, model-free linkage analyses of large pedigrees from Iceland, a geographical isolate, revealed 26 loci suggestive of linkage. In stage II, ten of these were followed-up in a second international collaborative study comprising families from Austria, Canada, Germany, Italy, Scotland, Sweden, Taiwan and the United States. Potential linkage findings of stage I on chromosomes 6p, 9 and 20 were observed again in the second sample. Furthermore, in a third sample from China, fine mapping of the 6p region by association studies also showed evidence for linkage or linkage disequilibrium. Combining our results with other recent findings revealed significant evidence for linkage to an area distal of the HLA region on chromosome 6p. However, in a fourth sample from Europe, the 6p fine mapping finding observed in the Chinese sample could not be replicated. Finally, evidence suggestive of locus heterogeneity and oligogenic transmission in schizophrenia was obtained.

Although reactive oxygen species (ROS) contribute to glucose intolerance induced by the renin-angiotensin system (RAS) is well documented, the role of the newly discovered pathway of RAS, angiotensin (Ang)-(1-7)/Mas axis, in this process remains unknown. Here, we examined the effect of Ang-(1-7) on oxidative stress and glucose uptake in adipocytes. We used primary cultured epididymal adipocytes from C57 mice to study Ang-(1-7) effects on glucose uptake. We also treated fully differentiated 3T3-L1 adipocytes with exogenous Ang-(1-7) or overexpression of angiotensin-converting enzyme 2 (ACE2) to induce endogenous generation of Ang-(1-7) to clarify its effects on ROS production. Intracellular ROS was measured by flow cytometry, dihydroethidium (DHE), and nitroblue tetrazolium assay. Levels of NADPH oxidase and adiponectin mRNA were measured by real-time PCR. Ang-(1-7) improved glucose uptake both in basal and insulin-stimulated states. ROS production was slightly but significantly decreased in adipocytes treated with Ang-(1-7). Additionally, Mas receptor antagonist D-Ala7-Ang-(1-7) (A779) reversed the effect of Ang-(1-7) on glucose uptake and oxidative stress. Furthermore, treatment of adipocytes with Ang-(1-7) decreased NADPH oxidase mRNA levels. We also found that oxidative stress induced by glucose oxidase-suppressed expression of adiponectin, an insulin-sensitive protein. However, the suppression of oxidative stress by Ang-(1-7) restored adiponectin expression, while A779 agonists these changes induced by Ang-(1-7). In conclusion, Ang-(1-7) can protect against oxidative stress and improve glucose metabolism in adipocytes. These results show that Ang-(1-7) is a novel target for the improvement of glucose metabolism by preventing oxidative stress.