Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011881 (diabetic nephropathy)
 10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

High extracellular glucose plays a pivotal role in the pathophysiology of diabetic nephropathy. Here we report 200 genes, identified using suppression-subtractive hybridization, that are differentially expressed when human mesangial cells are propagated in high ambient glucose in vitro. The major functional classes of genes identified included modulators and products of extracellular matrix protein metabolism, regulators of cell growth and turnover, and a cohort of actin cytoskeleton regulatory proteins. Actin cytoskeletal disassembly is a prominent feature of diabetic nephropathy. The induction of actin cytoskeleton regulatory gene expression by high glucose was attenuated by the inhibitor of reactive oxygen species generation, carbonyl cyanide m-chlorophenylhydrazone but not by the protein kinase C inhibitor GF 109203X and was not mimicked by the addition of transforming growth factor beta. Enhanced expression of actin cytoskeleton regulatory genes was also observed following disruption of the mesangial cell actin cytoskeleton by cytochalasin D. In aggregate, these results suggest that the induction of genes encoding actin cytoskeleton regulatory proteins (a) is a prominent component of the mesangial cell transcriptomic response in diabetic nephropathy and (b) is dependent on oxidative stress, is independent of protein kinase C and transforming growth factor-beta, and represents an adaptive response to actin cytoskeleton disassembly.
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PMID:High glucose-altered gene expression in mesangial cells. Actin-regulatory protein gene expression is triggered by oxidative stress and cytoskeletal disassembly. 1178 18

Hyperglycemia increases the production of reactive oxygen species (ROS) from the mitochondrial electron transport chain in bovine endothelial cells. Because several studies have postulated a role for prostaglandins (PGs) in the glomerular hyperfiltration seen in early diabetes, we evaluated the effect of mitochondrial ROS on expression of the inducible isoform of cyclooxygenase (COX-2) in cultured human mesangial cells (HMCs). We first confirmed that incubation of HMC with 30 mmol/l glucose significantly increased COX-2 mRNA but not COX-1 mRNA, compared with 5.6 mmol/l glucose. Similarly, incubation of HMCs with 30 mmol/l glucose significantly increased mitochondrial membrane potential, intracellular ROS production, COX-2 protein expression, and PGE2 synthesis, and these events were completely suppressed by thenoyltrifluoroacetone or carbonyl cyanide m-chlorophenylhydrazone, inhibitors of mitochondrial metabolism, or by overexpression of uncoupling protein-1 or manganese superoxide dismutase. Furthermore, increased expression of COX-2 mRNA and protein was confirmed in glomeruli of streptozotocin-induced diabetic mice. In addition, hyperglycemia induced activation of the COX-2 gene promoter, which was completely abrogated by mutation of two nuclear factor kappaB (NF-kappaB) binding sites in the promoter region. Our results suggest that hyperglycemia increases mitochondrial ROS production, resulting in NF-kappaB activation, COX-2 mRNA induction, COX-2 protein production, and PGE2 synthesis. This chain of events might contribute to the pathogenesis of diabetic nephropathy.
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PMID:Reactive oxygen species from mitochondria induce cyclooxygenase-2 gene expression in human mesangial cells: potential role in diabetic nephropathy. 1451 42