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

Differential Display was used to isolate genes that show transcriptional changes in the kidney during the development of diabetes in the GK rat. Eight candidate diabetes-associated cDNA fragments, CDK1-8, were isolated and characterised. cDNA sequencing and subsequent database analysis revealed that CDK2, 4, 5 and 6 showed no significant sequence similarity to previously reported genes, suggesting that they represent novel genes, whereas CDK 1, 3, 7 and 8 showed significant similarity with rat lactate dehydrogenase, rat amiloride sensitive sodium channel, EST109013 and mouse ubiquitin-like protein respectively. The differential mRNA expression of CDK1-8 was confirmed using differential screening of slot blots. CDK1, 2, 4 and 8 mRNAs appeared to increase whereas CDK3, 5, 6 and 7 mRNAs decreased in the kidneys of GK rats with increasing hyperglycaemia. The altered renal mRNA expression of these genes in association with increased hyperglycemia in the GK rat suggest that they are candidates for a role in the development of diabetic nephropathy.
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PMID:Isolation of diabetes-associated kidney genes using differential display. 912 49

Hypertrophy of mesangial cells is an early hallmark of diabetic nephropathy. We have previously shown that murine mesangial cells (MMC), cultured in high-glucose medium, are arrested in the G1 phase of the cell cycle and undergo hypertrophy. This study was undertaken to test whether high glucose-containing medium influences the expression of p27Kip1, an inhibitor of G1 phase active cyclin-dependent kinases (CDK). Incubation of MMC, in the absence of other factors for 48-96 h, in medium containing high D-glucose (450 mg/dl), stimulated p27Kip1 protein expression but failed to influence mRNA abundance. These effects were independent of the osmolarity of the medium. High glucose-stimulated expression of p27Kip1 involved activation of protein kinase C and was partly dependent on induction of transforming growth factor-beta (TGF-beta). Immunoprecipitation experiments revealed that only small amounts of p27Kip1 protein from MMC grown in high-glucose medium preferentially associates with CDK2 but not with CDK4. The p27Kip1 antisense, but not missense, oligonucleotides inhibited high glucose-stimulated total protein synthesis and facilitated G1 phase exit. Our data showed for the first time that expression of p27Kip1 protein is pivotal in mesangial cell hypertrophy induced by high ambient glucose. These findings may be important in the deciphering of molecular processes causing diabetic glomerular hypertrophy.
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PMID:High glucose stimulates expression of p27Kip1 in cultured mouse mesangial cells: relationship to hypertrophy. 932 7

Inhibitors of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, also known as statins, are lipid-lowering agents widely used in the prevention of coronary heart disease. Recent experimental and clinical data, however, indicate that the overall benefits of statin therapy may exceed its cholesterol-lowering properties. We postulate that statins may ameliorate the detrimental effects of high glucose (HG)-induced proliferation of mesangial cells (MCs), a feature of early stages of diabetic nephropathy, by preventing Rho isoprenylation. Rat MCs cultured in HG milieu were treated with and without simvastatin, an HMG-CoA reductase inhibitor. Simvastatin inhibited HG-induced MC proliferation as measured by [(3)H]thymidine incorporation. This inhibitory effect was reversed with geranylgeranyl pyrophosphate, an isoprenoid intermediate of the cholesterol biosynthetic pathway. At the cell-cycle level, the HG-induced proliferation of MCs was associated with a decrease in cyclin dependent kinase (CDK) inhibitor p21 protein expression accompanied by an increase in CDK4 and CDK2 kinase activities. Simvastatin reversed the down-regulation of p21 protein expression and decreased CDK4 and CDK2 kinase activities. Exposure of MCs to HG was associated with an increase in membrane-associated Ras and Rho GTPase protein expression. Cotreatment of MCs with simvastatin reversed HG-induced Ras and Rho membrane translocation. Immunofluorescence microscopy revealed that the overexpression of the dominant-negative RhoA led to a significant increase in p21 expression. Our data suggest that simvastatin represses the HG-induced Rho GTPase/p21 signaling in glomerular MCs. Thus, this study provides a molecular basis for the use of statins, independently of their cholesterol-lowering effect, in early stages of diabetic nephropathy.
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PMID:3-Hydroxy-3-methylglutaryl CoA reductase inhibitors prevent high glucose-induced proliferation of mesangial cells via modulation of Rho GTPase/ p21 signaling pathway: Implications for diabetic nephropathy. 1204 57

Connective tissue growth factor (CTGF) is now considered to be one of the important driver molecules for the pathogenesis of diabetic nephropathy (DN) and possibly many other fibrotic disorders. However, the molecular mechanisms by which CTGF functions remain to be established. In an attempt to define these mechanisms, this study was designed to investigate whether CTGF has any effect on the cell cycle of human mesangial cells (HMC), which are known to undergo hypertrophy in DN. This report provides the first evidence that CTGF is a hypertrophic factor for HMC. CTGF stimulates HMC to actively enter the G(1) phase from G(0), but they do not then progress further through the cell cycle. The molecular mechanisms underlying this G(1) phase arrest appear to be due to the induction of the cyclin-dependent kinase inhibitors (CDKI) p15(INK4), p21(Cip1), and p27(Kip1), which are known to bind and inactivate cyclinD/CDK4/6 and the cyclin E/CDK2 kinase complexes. This could account for the maintenance of pRb protein in a non- or very low-phosphorylated state, preventing cell cycle progression. Using CTGF antisense oligonucleotides, the results also indicate that the previously identified transforming growth factor-beta (TGF-beta)-induced hypertrophy in mesangial cells is CTGF-dependent. Mesangial cell hypertrophy is one of the earliest abnormalities of diabetic nephropathy; therefore, therapeutic strategies targeting CTGF may be beneficial in controlling DN.
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PMID:Connective tissue growth factor and regulation of the mesangial cell cycle: role in cellular hypertrophy. 1223 52

Loss of podocytes is an early feature of diabetic nephropathy (DN) and predicts its progression. We found that treatment of podocytes with sera from normoalbuminuric type 1 diabetes patients with high lipopolysaccharide (LPS) activity, known to predict progression of DN, downregulated CDK2 (cyclin-dependent kinase 2). LPS-treatment of mice also reduced CDK2 expression. LPS-induced downregulation of CDK2 was prevented in vitro and in vivo by inhibiting the Toll-like receptor (TLR) pathway using immunomodulatory agent GIT27. We also observed that CDK2 is downregulated in the glomeruli of obese Zucker rats before the onset of proteinuria. Knockdown of CDK2, or inhibiting its activity with roscovitine in podocytes increased apoptosis. CDK2 knockdown also reduced expression of PDK1, an activator of the cell survival kinase Akt, and reduced Akt phosphorylation. This suggests that CDK2 regulates the activity of the cell survival pathway via PDK1. Furthermore, PDK1 knockdown reduced the expression of CDK2 suggesting a regulatory loop between CDK2 and PDK1. Collectively, our data show that CDK2 protects podocytes from apoptosis and that reduced expression of CDK2 associates with the development of DN. Preventing downregulation of CDK2 by blocking the TLR pathway with GIT27 may provide a means to prevent podocyte apoptosis and progression of DN.
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PMID:Cyclin-dependent kinase 2 protects podocytes from apoptosis. 2687 72