DESCRIPTION (provided by applicant):In North America, diabetes mellitus (DM) is the leading cause of end stage kidney disease (ESRD). Prominent histologic features of diabetic nephropathy include podocyte loss, mesangial cell (MC) hypertrophy, mesangial matrix expansion, basement membrane thickening and tubulointerstitial fibrosis. Persistent albuminuria, believed to be the result of injury to podocytes, is a major clinical hallmark of diabetic nephropathy. Podocytes form part of the perm-selectivity barrier in the kidney and the podocytes-specific protein, nephrin, plays a cardinal role in the function of the permeability barrier. The MC-specific protein megsin, a serine protease inhibitor, may be important in matrix remodeling and maintenance. Although blood glucose control is critically related to albuminuria, the mechanisms by which DM causes kidney injury have not been fully elucidated. Studies have shown that maneuvers like overexpression of glutamine:fructose-6-phosphate amidotransferase (GFAT), or exposure of MC to glucosamine, upregulates the expression of genes that have been implicated in renal injury; [GFAT is the rate limiting enzyme for glucose entry in the hexosamine pathway; glucosamine is downstream of GFAT in this pathway]. My hypothesis is that increased flux through the hexosamine pathway is one mechanism whereby DM may cause kidney disease. The major objective of my study is to use gene-targeting technology to develop mice that will express the GFAT protein in podocytes and MC under the control of the promoters for nephrin and megsin respectively, and to determine how this may modulate susceptibility to kidney injury following induction of DM with streptozotocin. I will compare the renal physiology and morphology of diabetic and non-diabetic targeted and wildtype mice of the same strain to ascertain whether increased activity of the hexosamine pathway predisposes mice to kidney injury and glomerulosclerosis. If my hypothesis is correct, this in vivo overexpression of GFAT will lead to kidney damage in non-diabetic mice and to enhancement of that caused by DM. These studies should further our understanding of the role of the hexosamine pathway in diabetic nephropathy, and may also provide a new animal model, in which to study diabetic nephropathy and its associated vascular complications.
- National Institute of Diabetes and Digestive and Kidney Diseases
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