The Thioredoxin System in Diabetic Nephropathy

32 Hyperhexosemia-Induced Vasoactive Factors and Extracellular Matrix Protein Production in Kidneys are Mediated via NFB. BRADLEY J. DE SOUZA, JANE CHIU, BIAO FENG, BIJU GEORGE AND SUBRATA CHAKRABARTI, Department of Pathology, University of Western Ontario, London, ON Increase in reactive oxygen species production, in diabetes, is critical in the initiation of the cellular responses by activating redox-sensitive transcription factor, nuclear factor kappa B (NFB). NFB activation may lead to cellular structural and functional alteration via altered expression of cytokines. We investigated the role of NFB in the development of early changes in diabetic nephropathy We used a hyperhexosemic, normoinsulinimic model of chronic diabetic complication to avoid potential problems associated with systemic insulin therapy needed for longterm diabetic animals. Hence, NFB(p50) knockout mice and their wild-type controls were fed with a 30% galactose diet for 2 months. Renal tissues were analyzed. Galactose-fed animals showed increased in serum reducing sugars, without any alterations of body weight. Wild type galactose-fed animals demonstrated increase in the mRNA expression of ET-1 and TGF1. Furthermore ECM proteins, regulated by ET-1 and TGF 1, such as fibronectin and collagen1 4 were upregulated. Interestingly, poly ADP ribose polymerase mRNA expression was not altered. Such alterations were prevented in the kidneys of galactose-fed knockout animals. These results demonstrate that early changes in diabetic nephropathy may be mediated through NFB-dependent signaling pathways. Understanding these mechanisms is important in identifying potential novel treatment targets. Supported by CDA