Our current research efforts are focused on metabolic and physiologic processes that may influence the pathogenesis of diabetic kidney disease. Hyperglycemia plays a pivotal role in the pathogenesis of diabetic micro- and macro-vascular complications, but is insufficient to account for all of the complications of diabetes mellitus. In this regard, flux through the hexosamine pathway may mediate some adverse consequences of hyperglycemia. We have found that increased flux through the hexosamine pathway increases pro-fibrotic proteins (PAI-1, TGF-beta1) and NF-kB-dependent gene expression. To further explore mechanism(s) of progressive kidney disease, ongoing research utilize transgenic mice in which enzymes in the hexosamine pathway are targeted to glomerular cells to study the hexosamine pathway’s role in modulating susceptibility to diabetic glomerulopathy. In addition, these studies will aid our understanding of how products of the hexosamine pathway (glucosamine, N-acetyl glucosamine) may interact with cytokines like connective tissue growth factor (CTGF) to modulate disease progression. A closely related aspect of our research entails examination of the consequence(s) of variable expression (1 to 4 copies) of the cytokine connective tissue growth factor (CTGF) on blood pressure and kidney function and susceptibility to proteinuric kidney disease. Cells (mesangial cells, podocytes, embryonic fibroblasts) from the latter line of mice are being used to study signaling responses to high glucose and hexosamine pathway metabolites.
RESEARCH INTERESTS
Hexosamine Pathway relationship to injury
Diabetic Kidney Disease
Signaling response to hyperglycemia
RECENT PUBLICATIONS
Krepinsky J, Ingram AJ, James LR, et al., "17-beta-estradiol modulates mechanical strain-induced MAPK activation in mesangial cells" J Biol Chem, 277:9387-9394, 2002
Caron KM, James LR, Kim HS, Knowles J, Uhlir R, Mao L, Hagaman JR, Cascio W, Rockman H, Smithies O, "Cardiac hypertrophy and sudden death in mice with a genetically clamped renin transgene" Proc Natl Acad Sci USA, 10:3106-3111, 2004
Ingram AJ, Krepinsky L, James L, Austin RC, Tang D, Salapatek AM, Thai K, Scholey JW, "Activation of mesangial cell MAPK in response to homocysteine" Kidney Int, 66:733-745, 2004
Caron KM, James LR, Lee G, Kim HS, Smithies O, "Lifelong Genetic Minipumps" Physiol Genomics, 20:203-209, 2005
Shastry S, Ingram AJ, Scholey JW, James LR, "Homocysteine Induces Mesangial Cell Apoptosis via Activation of p38-MAPK" 2007, Kidney International, 71:304-311, 2007
SIGNIFICANT PUBLICATIONS
James LR, Fantus IG, Goldberg H, et al., "Overexpression of glutamine: fructose-6-phosphate amindotransferase (GFAT) activates the plasminogen activator inhibitor type I (PAI-1) promoter" Am J Physiol Renal Physiol, 279:F717 - F727, 2000
James LR, Ingram A, Ly H, et al., "Angiotensin II activates the GFAT promoter in mesangial cells" Am J Physiol Renal Physiol, 281:F151 -F162, 2001
James LR, Tang D, Ingram A, et al., "Flux through the hexosamine pathway is a determinant of NF-kB-dependent promoter activation" 2002, Diabetes, 51:1146 - 1156
Caron KM, James LR, Kim HS, et al., "A genetically clamped renin transgene for the induction of hypertension" Proc Natl Acad Sci USA, 99:8248-8252, 2002
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