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)

Reactive oxygen species contribute to glomerular damage and proteinuria. In this study, we show that cultured human podocytes produce superoxide in response to extracellular adenosine triphosphate (ATP), and we identified the oxidases involved in this process. Adenosine triphosphate (10-4 M for 4 hr) raised superoxide production from 1.28 +/- 0.15 to 2.67 &/- 0.34 nmol/mg protein/min. Studies with podocyte homogenates revealed activation of both nicotinamide adenine dinucleotide (NADH; from 2.65 +/- 0.23 to 7.43 +/- 0.57) and nicotinamide adenine dinucleotide phosphate (NADPH) dependent oxidases [from 1.74 +/- 0.13 to 4.05 +/- 0.12 (nmol O2/mg protein/min)] by ATP. Activity of xanthine-oxidases was low and unchanged by ATP. Activation of the plasma-membrane bound NAD(P)H oxidases by ATP was time and dose dependent. Reverse transcribed-polymerase chain reaction (RT-PCR) studies with primers derived from monocyte sequences amplified mRNA for the NADPH oxidase subunits p22phox, p47phox, gp91phox, and p67phox, and the latter was transiently increased by ATP. Experiments with actinomycin D and cycloheximide suggested that ATP modulates enzyme activity at the transcriptional and translational levels. In conclusion, NAD(P)H dependent, membrane associated oxidases represent the major superoxide source in human podocytes. Activation of NAD(P)H oxidase by ATP might be secondary to increased mRNA expression of the NADPH oxidase subunit gp67phox.
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PMID:NAD(P)H oxidase activity in cultured human podocytes: effects of adenosine triphosphate. 950 11

Chronic nitric oxide (NO) synthase inhibition in rats causes hypertension, renal vascular injury, and proteinuria. NO deficiency increases superoxide (O(2)(-)) activity, but the effects of antioxidant treatment on renal injury have not been studied in this model. Exposure of rats to N omega-nitro-L-arginine (L-NNA) for 4 d markedly decreased NO-dependent relaxation in aortic rings and increased glomerular and renal interstitial monocyte influx, but renal O(2)(-) activity was not increased. After 7 d, BP and proteinuria were significantly increased. After 21 d of L-NNA treatment, rats displayed severe hypertension, decreased GFR, marked proteinuria, glomerular ischemia, renal vascular and tubulointerstitial injury, and complete loss of NO-dependent relaxation. Renal O(2)(-) activity was markedly increased [lucigenin-enhanced chemiluminescence (LEC), 279 +/- 71 versus 50 +/- 7 counts/10 mg, P < 0.01; electron paramagnetic resonance spectroscopy, 0.57 +/- 0.05 versus 0.34 +/- 0.04 U/10 mg, P < 0.05]. Apocynin, a specific inhibitor of NADPH oxidase, and diphenyleneiodonium, an inhibitor of flavin-containing enzymes, completely inhibited LEC signals in vitro, whereas allopurinol had no effect, indicating that NAD(P)H oxidase plays a major role in superoxide production in the kidney. Endothelial function remained impaired during cotreatment with alpha-tocopherol and there was no effect on hypertension or tubulointerstitial injury, but glomerular ischemia, decreases in GFR, and renal vascular injury were prevented and proteinuria was ameliorated. Renal LEC signals were intermediate between control and L-NNA-alone values (181 +/- 84 counts/10 mg). Chronic NO synthase inhibition in rats results in marked increases in renal cortical O(2)(-) activity, mediated by flavin-dependent oxidases. The absence of early increases in renal O(2)(-) activity, in the presence of endothelial dysfunction and macrophage influx, indicates that increased renal O(2)(-) activity is neither attributable to NO deficiency per se nor solely related to macrophage influx. The improvement of glomerular function and amelioration of renal vasculitis and proteinuria with vitamin E cotreatment indicate that oxidants are involved in the pathogenesis of renal injury in this model. However, markedly impaired endothelial function and unabated hypertension persist with vitamin E treatment and seem to be directly attributable to NO deficiency.
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PMID:Vitamin E alleviates renal injury, but not hypertension, during chronic nitric oxide synthase inhibition in rats. 1172 26

In the rat passive Heymann nephritis model of membranous nephropathy, complement C5b-9 induces sublethal glomerular epithelial cell (GEC) injury and proteinuria. C5b-9 activates cytosolic phospholipase A(2) (cPLA(2)), and products of cPLA(2)-mediated phospholipid hydrolysis modulate GEC injury and proteinuria. In the present study, we demonstrate that C5b-9 activates c-Jun N-terminal kinase (JNK) in cultured rat GECs and that JNK activity is increased in glomeruli isolated from proteinuric rats with passive Heymann nephritis, as compared with control rats. Stable overexpression of cPLA(2) in GECs amplified complement-induced release of arachidonic acid (AA) and JNK activity, as compared with neo (control) GECs. Activation of JNK was not affected by indomethacin. Incubation of GECs with complement stimulated production of superoxide, and pretreatment with the antioxidants, N-acetylcysteine, glutathione, and alpha-tocopherol as well as with diphenylene iodonium, an inhibitor of the NADPH oxidase, inhibited complement-induced JNK activation. Conversely, H(2)O(2) activated JNK, whereas exogenously added AA stimulated both superoxide production and JNK activity. Overexpression of a dominant-inhibitory JNK mutant or treatment with diphenylene iodonium exacerbated complement-dependent GEC injury. Thus, activation of cPLA(2) and release of AA facilitate complement-induced JNK activation. AA may activate the NADPH oxidase, leading to production of reactive oxygen species, which in turn mediate the activation of JNK. The functional role of JNK activation is to limit or protect GECs from complement attack.
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PMID:Complement activates the c-Jun N-terminal kinase/stress-activated protein kinase in glomerular epithelial cells. 1219 30

An imbalance between production of reactive oxygen species (ROS) and antioxidant defense is involved in the pathogenesis of diverse chronic parenchymatous diseases. To identify the primary site of such increased oxidative stress, a lipophilic ROS-sensitive probe (C11-Bodipy 581/591) is introduced, which allows the visualization and quantification of oxidative injury using confocal fluorescence microscopy in living cells. The properties of this probe are such that its emission wavelength irreversibly shifts from red to green upon oxidation. This probe was used to identify the spatiotemporal distribution of lipid peroxidation in the rat kidney during chronic NOS inhibition, a model associated with hypertension and proteinuria. Chronic NOS inhibition resulted in increased lipid peroxidation in renal tubules but hardly any in glomeruli or blood vessels. This peroxidation preceded the loss of renal function characteristic of the model and was accompanied by parallel changes in thiobarbituric acid reactive substances in the renal cortex. Furthermore, the increase in oxidation was dependent on angiotensin II and NADPH oxidase and prevented by vitamin E. Induction of cytoprotective heat-shock protein 70 preceded lipid peroxidation, rise in BP, or proteinuria. These findings challenge the paradigm that the vascular wall is the source and target of oxidative stress in chronic parenchymatous renal disease associated with hypertension.
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PMID:Visualizing tubular lipid peroxidation in intact renal tissue in hypertensive rats. 1244 19

Renal proximal tubular cells activated by reabsorption of protein are thought to play significant roles in the progression of kidney diseases. It was hypothesized that the signal transducer and activator of transcription (STAT) proteins may be activated by proteinuria in proximal tubular cells. To test this hypothesis, murine proximal tubular cells were treated with albumin (30 mg/ml medium) for various lengths of time. The results showed that albumin could activate Stat1 and Stat5 within 15 min in proximal tubular cells. The activation of STATs was mediated mostly by Jak2 and required no protein synthesis. In addition, activation of Stat1 occurred even after neutralization of IFN-gamma. The activation of STATs was inhibited by N-acetyl-L-cysteine, a precursor of glutathione and a reactive oxygen species (ROS) scavenger, and fluorescence-activated cell sorter analysis showed upregulation of intracellular ROS after albumin overloading, suggesting that albumin per se could generate ROS in proximal tubular cells. The activation of STATs occurred by way of the ROS generating system, and especially through the membrane-bound NADPH oxidase system. Reduced activities of glutathione peroxidase and catalase could also be responsible for the accumulation of intracellular ROS. Hence, not only the ROS generating system, but also the ROS scavenging system may contribute to the induction of ROS by albumin. These findings support the hypothesis that proximal tubular cells are activated and generate ROS by reabsorption of abundant urinary proteins filtered through the glomerular capillaries, and as a consequence, various IFN-gamma-inducible proteins are synthesized through IFN-gamma-independent activation of STAT signaling.
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PMID:Activation of the signal transducer and activator of transcription signaling pathway in renal proximal tubular cells by albumin. 1474

Our recent efforts have been focused on the mechanisms responsible for the progression of aldosterone-induced renal injury. We have demonstrated in rats that chronic treatment with aldosterone (0.75 micro g/H, SC) and 1% NaCl (in drinking solution) results in severe proteinuria and glomerular injury, characterized by cell proliferation and mesangial matrix expansion. Increased renal cortical NAD(P)H oxidase expression, reactive oxygen species (ROS) generation, and mitogen-activated protein kinase (MAPK) activation were also observed. Treatment with a selective mineralocorticoid receptor antagonist, eplerenone(0.125% in chow), or an antioxidant, tempol (3 mM in drinking solution), prevented elevations of ROS levels and MAPK activity, as well as ameliorating glomerular injury, indicating that aldosterone-induced glomerular injury is associated with redox-sensitive MAPK activation. In vitro studies showed that mineralocorticoid receptors are highly expressed in rats mesangial cells, particularly in the cytoplasm. Aldosterone (100 nM) application activates MAPK and causes cellular proliferation and deformation. These data suggest that aldosterone contributes to the progression of glomerular injury through its direct actions.
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PMID:Aldosterone and renal injury. 1527 28

Wild-type mice are resistant to ANG II-induced renal injury and hence form an attractive model to study renal defense against ANG II. The present study tested whether ANG II induces expression of antioxidative genes via the AT2 receptor in renal cortex and thereby counteracts prooxidative forces. ANG II was infused in female C57BL/6J mice for 28 days and a subgroup received AT2 receptor antagonist (PD-123,319) for the last 3 days. ANG II induced hypertension and aortic hypertrophy; proteinuria and renal injury were absent. Urinary nitric oxide metabolites (NOx) were decreased, and lipid peroxide (TBARS) excretion remained unchanged. Expression of NADPH oxidase components was decreased in renal cortex but induced in aorta. Heme oxygenase-1 (HO-1) was induced in both renal cortex and aorta. In contrast, ANG II suggestively increased AT2 receptor expression in kidney but not in aorta. AT2 receptor blockade enhanced hypertension in ANG II-infused mice, reversed ANG II effects on NOx excretion, but did not affect TBARS. Despite its prohypertensive effect, expression of prooxidative genes in the renal cortex decreased rather than increased after short-term AT2 receptor blockade and renal HO-1 induction after ANG II was normalized. Thus chronic ANG II infusion in mice induces hypertension but not oxidative stress. In contrast to the response in aorta, gene expression of components of NADPH-oxidase was not enhanced in renal cortex. Although ANG II administration induced renal cortical AT2 receptor expression, blockade of that receptor did not unveil the AT2 receptor as intrarenal dampening factor of prooxidative forces.
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PMID:Resistance to oxidative stress by chronic infusion of angiotensin II in mouse kidney is not mediated by the AT2 receptor. 1572 90

Emerging clinical and experimental evidence strongly implicates proteinuria in the progression of kidney disease. One pathway involves the activation of NFkappaB by albumin, and it has been demonstrated that the activation of NFkappaB induced by albumin is dependent on mitogen-activated protein kinase ERK1/ERK2. To study the effect of albumin on gene expression, primary human renal tubular cells were exposed in vitro to albumin (1%) for 6 h, and gene expression profiling was performed with the human oligonucleotide microarray, U133A Affymetrix Gene Chip. In all, 223 genes were differentially regulated by albumin, including marked upregulation of the EGF receptor (EGFR) and IL-8. Accordingly, the authors sought to delineate the signaling pathway linking albumin to the EGFR and activation of ERK1/ERK2. It was found that albumin led to a dose- and time-dependent activation of ERK1/ERK2. Treatment with albumin led to EGFR phosphorylation, but the activation of ERK1/ERK2 was prevented by pretreatment of the cells with AG-1478, the EGFR kinase inhibitor, at a dose that inhibited EGF-induced ERK1/ERK2 activation. Exogenously administered reactive oxygen species (ROS) were found to activate ERK1/ERK2 via the EGFR and src tyrosine kinase activity and pretreatment of cells with the antioxidant N-acetylcysteine (NAC) and the NADPH oxidase inhibitor DPI abrogated albumin-induced activation of ERK1/ERK2. The src tyrosine kinase inhibitor, PP2, also inhibited the albumin-induced activation of ERK1/ERK2. Finally, pretreatment with AG-1478, the MEK inhibitor UO126, and NAC prevented the albumin-induced increase in IL-8 expression. The authors conclude that the EGF receptor plays a central role in the signaling pathway that links albumin to the activation of ERK1/ERK2 and increased expression of IL-8. Gene profiling studies suggest that there may be a positive feedback loop through the EGFR that amplifies the response of the proximal tubule cell to albumin. Taken together, these results suggest that the EGFR may be an important treatment target for kidney disease associated with proteinuria.
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PMID:Albumin activates ERK via EGF receptor in human renal epithelial cells. 1582 4

Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. Active and passive Heymann nephritis (HN) in rats are valuable experimental models because their features so closely resemble human MN. In HN, subepithelial immune deposits form in situ as a result of circulating antibodies. Complement activation leads to assembly of C5b-9 on glomerular epithelial cell (GEC) plasma membranes and is essential for sublethal GEC injury and the onset of proteinuria. This review revisits HN and focuses on areas of substantial progress in recent years. The response of the GEC to sublethal C5b-9 attack is not simply due to disruption of the plasma membrane but is due to the activation of specific signaling pathways. These include activation of protein kinases, phospholipases, cyclooxygenases, transcription factors, growth factors, NADPH oxidase, stress proteins, proteinases, and others. Ultimately, these signals impact on cell metabolic pathways and the structure/function of lipids and key proteins in the cytoskeleton and slit-diaphragm. Some signals affect GEC adversely. Thus C5b-9 induces partial dissolution of the actin cytoskeleton. There is a decline in nephrin expression, reduction in F-actin-bound nephrin, and loss of slit-diaphragm integrity. Other signals, such as endoplasmic reticulum stress, may limit complement-induced injury, or promote recovery. The extent of complement activation and GEC injury is dependent, in part, on complement-regulatory proteins, which act at early or late steps within the complement cascade. Identification of key steps in complement activation, the cellular signaling pathways, and the targets will facilitate therapeutic intervention in reversing GEC injury in human MN.
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PMID:Experimental membranous nephropathy redux. 1615

Endothelial dysfunction (ED) complicates hypertension and is a precursor of atherosclerosis. Reduced NO bioactivity, because of increased reduced NAD(P)H oxidase-derived reactive oxygen species (ROS), plays a critical role in ED. gp91phox, predominantly expressed in the endothelium and adventitia, is a subunit of NAD(P)H oxidase important for its activation in response to angiotensin (Ang) II. Human atherosclerotic plaques are heavy laden with gp91phox. We have shown that in Dahl salt-sensitive (DS) rats, a paradigm of low renin salt-sensitive (SS) hypertension in humans, Ang II receptor blockade normalizes ROS production and endothelium-dependent relaxation (EDR) without significantly affecting systolic blood pressure (SBP). To additionally elucidate the mechanisms involved in the functional association of Ang II in SS hypertension, we administered a cell-permeable inhibitor of the assembly of p47phox with gp91phox in NAD(P)H oxidase, gp91ds-tat (10 mg/kg body weight, 3 weeks by minipump), to DS rats fed a 4% salt diet. Control rats received either vehicle or an inactive scramb-tat peptide. Vehicle-treated DS developed hypertension (SBP 168+/-5 mm Hg), left ventricular hypertrophy (LVH), proteinuria, impaired EDR, and increased aortic ROS production (superoxide 115% and peroxynitrite 157%) and expression of the proatherogenic molecules LOX-1 (130%) and MCP-1 (166%). gp91ds-tat, but not scramb-tat, normalized ROS and EDR, as well as LOX-1 and MCP-1, despite nonsignificant effects on SBP (159+/-5 mm Hg; P>0.05), left ventricular hypertrophy, and proteinuria. Our findings support the notion that in SS hypertension, activation of NAD(P)H oxidase promotes ED and atherogenesis via decreased nitric oxide bioactivity and increased LOX-1 and MCP-1, independent of blood pressure.
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PMID:Reduced NAD(P)H oxidase in low renin hypertension: link among angiotensin II, atherogenesis, and blood pressure. 1634 66


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