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)

Early diabetes mellitus is characterized by an increase in glomerular filtration rate and effective renal plasma flow which may initiate and potentiate glomerular injury which ultimately results in diabetic nephropathy. To investigate the role of hyperglycemia per se in mediating these hemodynamic changes, eight healthy adults had inulin clearance, creatinine clearance, and para-aminohippurate (PAH) clearance after steady state conditions of hyperglycemia were achieved (549 +/- 86). Clearances were repeated during equivalent osmotic diuresis with Mannitol. Euvolemia was maintained by quantitative fluid and electrolyte replacement of urinary losses. Mean inulin clearances were 87 +/- 6, 87 +/- 5, and 81 +/- 4 ml/min during control, glucose, and mannitol periods (p = ns). Creatinine clearance overestimated inulin clearance by 15-32% but there were no differences between control glucose and mannitol periods. PAH clearance fell from control values of 595 +/- 29 to 340 +/- 22 ml/min during hyperglycemia (p less than .05). During osmotic diuresis with mannitol PAH, clearance rose to control values. In vitro studies excluded the possibility that conjugation between glucose and PAH can explain the clearance results. These results in normal subjects documenting renal vasoconstriction with hyperglycemia are of particular interest in view of recent experimental data suggesting that failure to vasoconstrict characterizes the hemodynamics of early diabetes.
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PMID:Effects of hyperglycemia and mannitol infusions on renal hemodynamics in normal subjects. 212 74

Mannitol is widely used because of its osmotic diuretic action and its presumed antioxidant properties. In pre-existent renal dysfunction, however, mannitol may accumulate leading to potentially deleterious effects. We describe a 71-year-old woman with moderate chronic renal failure due to diabetic nephropathy who developed acute anuric renal failure after mannitol administration for post-traumatic reflex sympathetic dystrophy. After haemodialysis symptoms of acute renal failure rapidly disappeared with recovery of pre-existent renal function. Daily measurement of the osmolal gap as a simple and accurate way of monitoring patients receiving mannitol infusion is emphasized. A rapid increase in the osmolar gap should prompt adjustment of the dose or even discontinuation of mannitol, especially in the case of pre-existent risk factors.
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PMID:Mannitol-induced acute renal failure. 903 39

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

Glomerular matrix accumulation is a hallmark of diabetic nephropathy. We have recently shown that epidermal growth factor receptor (EGFR) transactivation mediates high glucose (HG)-induced collagen I upregulation through PI3K-PKCbeta1-Akt signaling in mesangial cells (MC). Phospholipase Cgamma1 (PLCgamma1) interacts with activated growth factor receptors and activates classic PKC isoforms. We thus studied its role in HG-induced collagen I upregulation in MC. Primary rat MC were treated with HG (30 mM) or mannitol as osmotic control. Protein kinase activation was assessed by Western blotting and collagen I upregulation by Northern blotting. Diabetes was induced in rats by streptozotocin. HG treatment for 1 h led to PLCgamma1 membrane translocation and Y783 phosphorylation, both indicative of its activation. Mannitol was without effect. PLCgamma1 Y783 phosphorylation was also seen in cortex and glomeruli of diabetic rats. HG induced a physical association between EGFR and PLCgamma1 as identified by coimmunoprecipitation. PLCgamma1 activation required EGFR kinase activity since it was prevented by the EGFR inhibitor AG1478 or overexpression of kinase-inactive EGFR (K721A). Phosphoinositide-3-OH kinase inhibition also prevented PLCgamma1 activation. HG-induced Akt S473 phosphorylation, effected by PKCbeta1, was inhibited by the PLCgamma inhibitor U73122. PLCgamma1 inhibition or downregulation by small interference RNA also prevented HG-induced collagen I upregulation. Our results indicate that EGFR-PLCgamma1 signaling mediates HG-induced PKCbeta1-Akt activation and subsequent collagen I upregulation in MC. Inhibition of EGFR or PLCgamma1 may provide attractive therapeutic targets for the treatment of diabetic nephropathy.
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PMID:EGFR-PLCgamma1 signaling mediates high glucose-induced PKCbeta1-Akt activation and collagen I upregulation in mesangial cells. 1960 47