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)

The activation of protein kinase C (PKC) found in diabetic glomeruli and glomerular mesangial cells cultured under high glucose conditions has been proposed to contribute to the development of diabetic nephropathy. However, the abnormalities distal to PKC have not been fully elucidated yet. Herein, we provide the evidence that mitogen-activated protein kinase (MAPK) cascade, an important kinase cascade downstream to PKC and an activator of cytosolic phospholipase A2 (cPLA2) by direct phosphorylation, is activated in glomeruli isolated from streptozotocin-induced diabetic rats. MAPK cascade was also activated in glomerular mesangial cells cultured under high glucose (27.8 mmol/l) conditions for 5 days, and the activation of MAPK cascade was inhibited by treating the cells with calphostin C, an inhibitor of PKC. Furthermore, the activities of cPLA2 also increased in cells cultured under the same conditions and this activation was inhibited by both calphostin C and PD 098059, an inhibitor of MEK (MAPK or extracellular signal-regulated kinase [ERK] kinase). These results indicate that MAPK cascade is activated in glomeruli and mesangial cells under the diabetic state possibly through the activation of PKC. Activated MAPK, in turn, may induce various functional changes of mesangial cells at least through the activation of cPLA2 and contribute to the development of diabetic nephropathy.
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PMID:Mitogen-activated protein kinase cascade is activated in glomeruli of diabetic rats and glomerular mesangial cells cultured under high glucose conditions. 913 54

The stimulation of prostaglandin E2 (PGE2) production in mesangial cells exposed to a high glucose level was studied from the viewpoint of its implication in the glomerular hyperfiltration in diabetic nephropathy. The basal PGE2 synthesis apparently increased in the cells on incubation with a high glucose level (20 mM) for 3-6 h. Under these conditions, secretory phospholipase A2 activity was not detected in the incubation medium, but cytosolic phospholipase A2 (cPLA2) activity in the cells increased time-dependently up to 6 h, compared with that with a normal glucose level (5 mM). However, no difference in the cPLA2 protein content between the two glucose levels was observed on immunoblot analysis, suggesting that the increased cPLA2 activity under high glucose conditions is not due to stimulation of de novo synthesis. Stimulation with a calcium ionophore markedly enhanced arachidonic acid liberation and PGE2 production by cells exposed to the high glucose level. Furthermore, mitogen-activated protein kinase (MAPK) activity increased time-dependently under high glucose conditions, the rate of increase being consistent with those in cPLA2 activity and PGE2 production under the same conditions. These data suggest that glucose-induced cPLA2 activation through MAPK activation is responsible for the enhancement of PGE2 production in mesangial cells.
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PMID:High glucose-induced cytosolic phospholipase A2 activation responsible for eicosanoid production in rat mesangial cells. 949 65

In view of the potential role of prostaglandins (PGs) in development of glomerular hyperfiltration leading to diabetic nephropathy, we studied the temporal relationship of the activity of cytosolic phospholipase A2 (cPLA2), a rate-limiting enzyme for eicosanoid biosynthesis, with hyperfiltration and the histological changes in glomeruli using OLETF rats, a model for non-insulin-dependent diabetes mellitus (NIDDM). Diabetes mellitus and associated histopathological changes, which developed spontaneously by 30-46 weeks after birth of OLETF rats, were accompanied by approximately 65% increase in glomerular cPLA2 activity that showed significant correlations with elevated plasma glucose levels and creatinine clearance. Moreover, mesangial cells cultured for 5 days with high glucose exhibited approximately 2-fold higher cPLA2 activity than those cultured with physiologic level of glucose. These data suggest that increased glomerular cPLA2 activity leads to production of PGs, which may promote the progression of early diabetic glomerular hyperfiltration and subsequent diabetic nephropathy.
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PMID:Increased glomerular cytosolic phospholipase A2 activity of OLETF rats with early diabetes. 1048 42

Glomerular visceral epithelial cells (GEC) or podocytes are highly differentiated, specialized cells that play a key role in the maintenance of glomerular permselectivity. Injury of GEC, leading to proteinuria, contributes to the pathogenesis of human and experimental glomerulopathies. Recent studies have demonstrated that stress proteins may be induced and may be involved in the modulation of GEC injury. The C5b-9 membrane attack complex of complement induces GEC injury and proteinuria in the passive Heymann nephritis (PHN) model of membranous nephropathy. C5b-9 induces upregulation of the endoplasmic reticulum (ER) stress proteins, bip and grp94, in part, via activation of cytosolic phospholipase A2. These ER stress proteins limit complement-mediated GEC injury. In experimental nephropathy associated with hyperlipidemia, and in experimental diabetic nephropathy, there is an upregulation of the ER heat shock protein (Hsp) 47, a chaperone protein involved in the synthesis or assembly of collagens. Hsp47 expression in GEC is associated with increased deposition of collagen, and glomerulosclerosis. Hsp27, a stress protein involved in actin polymerization, is localized in GEC, and its expression and activation are increased in the rat puromycin aminonucleoside model of focal segmental glomerulosclerosis, and in PHN. Hsp27 may preserve actin structure, and facilitates survival in the context of injury. Development of methods to induce expression/activation of stress proteins may eventually lead to novel approaches to the therapy of GEC injury and proteinuria.
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PMID:Stress proteins in glomerular epithelial cell injury. 1591 24

Chronic hyperglycaemia during diabetes leads to non-enzymatic glycation of proteins to form advanced glycation end products (AGEs) that contribute to nephropathy. In diabetes, renal Na+ K+ ATPase (NKA) activity is downregulated and phosphoinositide metabolism is upregulated. We examined the effects of AGEs on NKA activity in porcine LLC-PK1 and human HK2 proximal tubule epithelial cells. AGE-BSA increased cellular phosphoinositol 4,5 bisphosphate (PIP2) production as determined by immunofluorescence microscopy and thin layer chromatography. AGE-BSA (40 microM) induced 3H-arachidonic acid release and reactive oxygen species (ROS) production via cytosolic phospholipase A2 (cPLA2) activation. Within minutes, AGE-BSA significantly inhibited NKA surface expression and activity in a dose- and time-dependent manner as determined by immunofluorescence staining and [86Rb+] uptake, respectively, suggesting AGEs inhibit NKA by stimulating its endocytosis. The AGE-BSA-induced decrease in cell surface NKA was reversed by a cPLA2alpha inhibitor, neomycin, a PIP2 inhibitor, and PP2, a Src inhibitor. AGE-BSA increased binding of NKA to the alpha-adaptin but not beta2- or mu2-adaptin subunits of the AP-2 clathrin pit adaptor complex. Transfection of HK2 cells with PIP5Kgamma siRNA prevented AGE-BSA inhibition of NKA activity. AGEs may stimulate PIP5Kgamma to increase PIP2 production, which may enhance AP-2 localisation to clathrin pits, increase clathrin pit formation, enhance NKA cargo recognition by AP-2 and/or stimulate cPLA2alpha activity. These results suggest AGEs modulate arachidonic acid and phosphoinositide metabolism to inhibit NKA via clathrin-mediated endocytosis. Elucidation of new intracellular AGE signaling pathways may lead to improved therapies for diabetic nephropathy.
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PMID:Advanced glycation end products inhibit Na+ K+ ATPase in proximal tubule epithelial cells: role of cytosolic phospholipase A2alpha and phosphatidylinositol 4-phosphate 5-kinase gamma. 2043 73