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)

Accumulation of mesangial matrix is a pivotal event in the pathophysiology of diabetic nephropathy. The molecular triggers for matrix production are still being defined. Here, suppression subtractive hybridization identified 15 genes differentially induced when primary human mesangial cells are exposed to high glucose (30 mM versus 5 mM) in vitro. These genes included (a) known regulators of mesangial cell activation in diabetic nephropathy (fibronectin, caldesmon, thrombospondin, and plasminogen activator inhibitor-1), (b) novel genes, and (c) known genes whose induction by high glucose has not been reported. Prominent among the latter were genes encoding cytoskeleton-associated proteins and connective tissue growth factor (CTGF), a modulator of fibroblast matrix production. In parallel experiments, elevated CTGF mRNA levels were demonstrated in glomeruli of rats with streptozotocin-induced diabetic nephropathy. Mannitol provoked less mesangial cell CTGF expression in vitro than high glucose, excluding hyperosmolality as the key stimulus. The addition of recombinant CTGF to cultured mesangial cells enhanced expression of extracellular matrix proteins. High glucose stimulated expression of transforming growth factor beta1 (TGF-beta1), and addition of TGF-beta1 to mesangial cells triggered CTGF expression. CTGF expression induced by high glucose was partially suppressed by anti-TGF-beta1 antibody and by the protein kinase C inhibitor GF 109203X. Together, these data suggest that 1) high glucose stimulates mesangial CTGF expression by TGFbeta1-dependent and protein kinase C dependent pathways, and 2) CTGF may be a mediator of TGFbeta1-driven matrix production within a diabetic milieu.
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PMID:Suppression subtractive hybridization identifies high glucose levels as a stimulus for expression of connective tissue growth factor and other genes in human mesangial cells. 1002 5

Advanced glycosylation end products (AGE) seem to be implicated in the pathogenesis of diabetic nephropathy. The present study has examined the effects of AGE on protein kinase C (PKC) activity and transforming growth factor-beta1 (TGF-beta1) in relation to collagen gene regulation in cultured human mesangial cells (HMCs). Quiescent HMCs were exposed to serum-free media containing bovine serum albumin (BSA), AGE-modified BSA (AGE-BSA), or glycated BSA in which AGE formation was prevented by the use of aminoguanidine (BSA-AM). AGE-BSA (200 microg/mL) induced a peak membrane-associated PKC activity, particularly PKC-a, at 4 hours. AGE-BSA stimulated alpha1(I) and alpha1(IV) collagen mRNA expression after 24-hour incubation with HMCs, which remained elevated until hour 60. HMCs incubated with AGE-BSA induced a significant inhibition of cell proliferation compared with cells incubated with BSA. AGE-BSA stimulated TGF-beta mRNA and protein expression in HMCs. The TGF-beta secreted by HMCs was shown by CCL-64 mink lung cell assay to be bioactive. In contrast, BSA-AM did not affect either collagen or TGF-beta mRNA or protein expression in HMCs. The stimulatory effects of AGE-BSA on collagen gene regulation in HMCs could be negated by the pretreatment of HMCs with GF 109203X for 30 minutes or with phorbol myristate acetate for 24 hours before AGE-BSA administration. Neutralizing antibody to TGF-beta inhibited increased collagen mRNA expression by HMCs exposed to AGE-BSA. These results suggest that AGE-BSA stimulates collagen mRNA expression by activating PKC and the transcriptional upregulation of TGF-beta1 in HMCs. Thus, PKC and TGF-beta may function as key signaling intermediaries in the AGE-up-regulated collagen gene expression pathway in HMCs.
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PMID:Advanced glycosylation end products stimulate collagen mRNA synthesis in mesangial cells mediated by protein kinase C and transforming growth factor-beta. 1143 29

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