Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyperglycemia-induced oxidative stress and protein kinase C (PKC) activation are implicated in the development and progression of diabetic nephropathy. Although PKC activation under hyperglycemia largely is related to an increase in de novo synthesis of diacylglycerol (DAG), activation of PKC can be regulated sensitively by oxidative stress. We investigated the expression and translocation of PKC isoforms in streptozotocin (STZ)-induced diabetic rat glomeruli and tubules and the effect of an antioxidant taurine. Experimental diabetes was induced by intravenous injection of 50 mg/kg of STZ. Two days after STZ, diabetic rats were assigned to one of two groups: untreated or treated with taurine 1% in drinking water. Four weeks after STZ, PKC isoforms were measured by Western blot analysis in the isolated glomeruli and tubules. DAG-dependent PKC isoforms PKC-alpha, PKC-betaI, PKC-betaII, PKC-delta, and PKC-epsilon and DAG-independent PKC-zeta all were detected in control rat glomeruli and tubules. Streptozotocin increased plasma glucose from 167 +/- 11 mg/dL to 575 +/- 35 mg/dL (n = 9, P < 0.01) and lipid peroxidation from 1.9 +/- 0.2 nmol/mL to 4.2 +/- 0.6 nmol/mL (P < 0.05) and induced proteinuria. In diabetic glomeruli, membrane-associated PKC-delta and PKC-epsilon content increased 47% and 57% above control, and membrane PKC-betaI content decreased to 67% of control. The membrane-associated PKC-alpha, PKC-betaII, and PKC-zeta content were not influenced. Total PKC-delta (163%) and PKC-epsilon (157%) increased significantly in diabetic tubules. Taurine prevented proteinuria and effectively inhibited alterations in PKC-delta and PKC-epsilon of diabetic glomeruli and tubules at dose-inhibiting lipid peroxidation but not hyperglycemia. These data suggest that PKC-delta and PKC-epsilon are sensitively activated by hyperglycemia-induced oxidative stress in diabetic rat kidney.
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PMID:Activation of protein kinase c-delta and c-epsilon by oxidative stress in early diabetic rat kidney. 1157 56

Mechanisms for human membranous glomerulonephritis (MGN) remain elusive. Most up-to-date concepts still rely on the rat model of Passive Heymann Nephritis that derives from an autoimmune response to glomerular megalin, with complement activation and membrane attack complex assembly. Clusterin has been reported as a megalin ligand in immunodeposits, although its role has not been clarified. We studied renal biopsies of 60 MGN patients by immunohistochemistry utilizing antibodies against clusterin, C5b-9, and phosphorylated-protien kinase C (PKC) isoforms (pPKC). In vitro experiments were performed to investigate the role of clusterin during podocyte damage by MGN serum and define clusterin binding to human podocytes, where megalin is known to be absent. Clusterin, C5b-9, and pPKC-alpha/beta showed highly variable glomerular staining, where high clusterin profiles were inversely correlated to C5b-9 and PKC-alpha/beta expression (P=0.029), and co-localized with the low-density lipoprotein receptor (LDL-R). Glomerular clusterin emerged as the single factor influencing proteinuria at multivariate analysis and was associated with a reduction of proteinuria after a follow-up of 1.5 years (-88.1%, P=0.027). Incubation of podocytes with MGN sera determined strong upregulation of pPKC-alpha/beta that was reverted by pre-incubation with clusterin, serum de-complementation, or protein-A treatment. Preliminary in vitro experiments showed podocyte binding of biotinilated clusterin, co-localization with LDL-R and specific binding inhibition with anti-LDL-R antibodies and with specific ligands. These data suggest a central role for glomerular clusterin in MGN as a modulator of inflammation that potentially influences the clinical outcome. Binding of clusterin to the LDL-R might offer an interpretative key for the pathogenesis of MGN in humans.
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PMID:Glomerular clusterin is associated with PKC-alpha/beta regulation and good outcome of membranous glomerulonephritis in humans. 1677 1

Diabetes induces the activation of several protein kinase C (PKC) isoforms in the renal glomeruli. We used PKC-beta(-/-) mice to examine the action of PKC-beta isoforms in diabetes-induced oxidative stress and renal injury at 8 and 24 weeks of disease. Diabetes increased PKC activity in renal cortex of wild-type mice and was significantly reduced (<50% of wild-type) in diabetic PKC-beta(-/-) mice. In wild-type mice, diabetes increased the translocation of PKC-alpha and -beta1 to the membrane, whereas only PKC-alpha was elevated in PKC-beta(-/-) mice. Increases in urinary isoprostane and 8-hydroxydeoxyguanosine, parameters of oxidative stress, in diabetic PKC-beta(-/-) mice were significantly reduced compared with diabetic wild-type mice. Diabetes increased NADPH oxidase activity and the expressions of p47(phox), Nox2, and Nox4 mRNA levels in the renal cortex and were unchanged in diabetic PKC-beta(-/-) mice. Increased expression of endothelin-1 (ET-1), vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-beta, connective tissue growth factor (CTGF), and collagens IV and VI found in diabetic wild-type mice was attenuated in diabetic PKC-beta(-/-) mice. Diabetic PKC-beta(-/-) mice were protected from renal hypertrophy, glomerular enlargement, and hyperfiltration observed in diabetic wild-type mice and had less proteinuria. Lack of PKC-beta can protect against diabetes-induced renal dysfunction, fibrosis, and increased expressions of Nox2 and -4, ET-1, VEGF, TGF-beta, CTGF, and oxidant production.
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PMID:Reduction of diabetes-induced oxidative stress, fibrotic cytokine expression, and renal dysfunction in protein kinase Cbeta-null mice. 1706 50