UMLS:C0033687 - FACTA Search

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Query: UMLS:C0033687 (proteinuria)
24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Following experimental rhabdomyolysis, animals become resistant to heme protein-induced acute renal failure (ARF). The goals of this study were to: (a) ascertain whether this resistance, previously documented only in vivo, is expressed directly at the proximal tubular cell level; (b) determine whether heme proteinuria (vs. other consequences of rhabdomyolysis) is its trigger; and (c) ascertain some of its subcellular determinants. Rats were injected with a borderline toxic dose of glycerol and 24 hours later proximal tubular segments (PTS) were isolated for study. Their vulnerability to diverse forms of injury (FeSO4-induced oxidant stress, hypoxia, Ca2+ ionophore, cytochalasin D, PLA2) was compared to that found in normal PTS. Post-glycerol PTS manifested significant resistance to each insult (decreased lactate dehydrogenase +/- N-acetyl-beta-D-glucosaminidase release). Protection against FeSO4 was virtually complete and it was associated with a 50% decrease in membrane lipid peroxidation. No decrease in hydroxyl radical generation was noted during the FeSO4 challenge (salicylate trap assessment), suggesting a primary increase in membrane resistance to attack. That PLA2 addition caused less deacylation, plasma membrane enzyme (alanine aminopeptidase) release, and LDH leakage from post-glycerol versus normal tubules supported this hypothesis. To test whether cytoresistance was specifically triggered by heme proteins (vs. being a non-specific filtered protein effect, or a result of endotoxin cascade activation), rats were injected with purified myoglobin, non-heme containing filterable proteins, or endotoxin. Only myoglobin induced cytoresistance. In vivo heme oxygenase inhibition (tin-protoporphyrin) did not block the emergence of cytoresistance and it was expressed despite Na,K-ATPase inhibition (ouabain) or cytoskeletal disruption (cytochalasin D). In vivo heat shock failed to protect. In conclusion, (1) rhabdomyolysis induces broad based proximal tubular cytoresistance; (2) heme proteinuria is its trigger; and (3) it is most easily explained by a primary increase in plasma membrane resistance to attack.
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PMID:Heme protein-induced tubular cytoresistance: expression at the plasma membrane level. 763 63

In glomerulonephritis, there is intraglomerular activation of inducible nitric oxide synthase (iNOS) leading to high output production of nitric oxide (NO). This can result in supraphysiologic amounts of NO and cause oxidative injury. It is unknown whether mechanisms of cellular defense against NO-mediated injury exist. Induction of the heme catabolizing enzyme heme oxygenase-1 (HO-1), which generates biliverdin, carbon monoxide (CO), and iron (Fe), may provide such a mechanism, as CO and Fe are two negative modulators of iNOS activity and expression. This study assessed whether upregulation of HO-1 by a specific inducer, hemin, negatively modulates iNOS expression and activity in anti-glomerular basement membrane antibody-mediated glomerulonephritis. Glomerular HO-1 expression in nephritic animals was upregulated by treatment with hemin (30 micromol/kg body wt). iNOS and HO-1 mRNA expression were assessed by reverse transcription-PCR of glomerular total RNA from nephritic animals or nephritic animals pretreated with hemin. iNOS activity in glomeruli was measured by assessing conversion of [14C] L-arginine to [14C] L-citrulline. HO-1 protein levels in glomeruli were assessed by Western blot analysis. The effect of hemin treatment on monocyte/macrophage infiltration was assessed by enumeration of ED-1-positive cells in nephritic glomeruli. iNOS and HO-1 were coinduced in nephritic glomeruli. Hemin treatment of nephritic animals resulted in upregulation of glomerular HO-1 levels and a two- to threefold reduction in glomerular iNOS mRNA levels. iNOS activity in glomeruli was significantly reduced in hemin-treated nephritic animals in which proteinuria was also attenuated without a change in monocyte/macrophage infiltration. Hemin (100 to 200 microM) also reduced iNOS protein levels and enzyme activity in cultured mesangial cells stimulated with cytokines. These studies demonstrate that in glomerular immune injury, hemin treatment upregulates glomerular HO-1 with an attendant downregulation of iNOS expression, and thus points to regulatory interaction between the two systems. The beneficial effect of hemin treatment on proteinuria could be linked to downregulation of iNOS.
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PMID:Heme oxygenase-1 induction attenuates inducible nitric oxide synthase expression and proteinuria in glomerulonephritis. 1058 93

In this study, we investigated the regulation and physiological role of heme oxygenase-1 (HO-1) in the kidney of rats with hypertension. Rats were continuously administered either angiotensin II (Ang II) or norepinephrine with an osmotic minipump for up to 7 days. Ang II infusion decreased the glomerular filtration rate (GFR) as determined through creatinine clearance (3.2+/-0.2 versus 1.2+/-0.2 mL/min with Ang II infusion, P<0.01) and increased proteinuria (9. 7+/-1.3 versus 28.1+/-7.2 mg/d with Ang II infusion, P<0.01). In contrast, norepinephrine did not alter these laboratory values. Ang II infusion significantly increased HO-1 expression in mRNA (442+/-98% of control at day 5, P<0.01) and protein levels (314+/-49% of control at day 5, P<0.01). Immunohistochemistry showed that in the kidney of normotensive rats, HO-1 was expressed mainly in the basal side in the renal tubules. After Ang II infusion, HO-1 staining was more extensively dispersed in the tubular epithelial cells. The intraperitoneal administration of zinc protoporphyrin, an HO inhibitor, to Ang II-infused rats further decreased GFR (0.8+/-0. 1 mL/min) and increased proteinuria (52.5+/-13.0 mg/d). In contrast, the administration of hemin, an HO inducer, ameliorated the Ang II-induced decrease in GFR (2.4+/-0.2 mL/min) and increase in proteinuria (9.3+/-4.5 mg/d). These data suggest that HO-1 upregulation in the kidney of Ang II-induced hypertensive rats may exert a renoprotective effect against Ang II-induced renal injury.
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PMID:Heme oxygenase-1 is upregulated in the kidney of angiotensin II-induced hypertensive rats : possible role in renoprotection. 1072 May 98

Transient sublethal hyperthermia followed by recovery from heat stress, referred to as heat shock preconditioning, exerts a protective effect on ischemia/reperfusion-induced injury in many systems. This effect is considered to be correlated to heat shock proteins (HSPs) and might be a critical factor in kidney graft function and survival. This study was designed to examine the impact of heat shock preconditioning on kidney isograft function and survival in a model utilizing non-heart-beating (NHB) donors. Four groups of male Lewis rats (n = 10/group) subjected either to whole body hyperthermia (groups A and C) or to sham anesthesia (groups B and D) were allowed 24 h recovery. Thereafter, 20 min of warm ischemia (A/B), and in a separate set of experiments 40 min of warm ischemia (C/D), were induced by suprarenal aortic cross clamping before renal procurement. After 24-h preservation with University of Wisconsin solution at 4 degrees C, orthotopic kidney transplantations were performed to syngeneic bilaterally nephrectomized recipients. Tissue specimens were taken to determine HO-1/HSP32, 72, and 90 induction by Western blot analysis. Renal function was measured by means of serum creatinine and creatinine clearance on days 0, 3, and 7 as well as urine volume, protein content, and creatinine levels daily. HO-1/HSP32 and HSP72 were found to be expressed constitutively. Moreover, heat shock strongly induced renal HSP72 and HSP32/HO-1, and to a lesser extent HSP90, expression. For recipients of group A grafts, the graft survival rate was 10/10, whereas it was 7/10 (70 %) in recipients of group B grafts (log rank p < 0.05). Following 40 min of warm ischemia, 6/10 (60 %) recipients survived, whereas all sham treated animals died with anuria within 6 days (log rank p = 0.01). Heat shock preconditioning strongly improved graft viability and reduced functional impairment. Creatinine clearance (CRC) on day 3 post Tx was 0.43 +/- 0.24 ml/min in preconditioned animals (group A) and 0.07 +/- 0.09 ml/min (p < 0.001) in sham preconditioned (group B), whereas it was 0.91 +/- 0.33 ml/min and 0.03 +/- 0.02 ml/min (p < 0.00 001) on day 7 post Tx. Following 40 min NHB time, CRC in survivors of preconditioned graft recipients (group C) was 0.32 +/- 0.2 ml/min (day 3 post Tx) and 0.23 +/- 0.08 ml/min (day 7 post Tx) and was significantly better than CRC of group B (p < 0.01 and p < 0.00001, respectively). CRCs prior to NHB procedures were comparable in all animals ranging between 1.31 and 1.72 ml/min. Serum creatinine as well as proteinuria were significantly increased after transplantation in both groups but recovered within 5 days in recipients of preconditioned grafts, whereas kidneys from donors without HP did not recover function. Histological alterations were also diminished following HP. Hyperthermic preconditioning induces strong and long lasting HO-1/HSP32, HSP72, and HSP90 expression in rat kidneys. HP increases survival following transplantation and improves renal graft function including proteinuria, volume output, and creatinine clearance. HSP induction might be used to develop novel approaches in clinical transplantation.
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PMID:Hyperthermia-induced HSP expression correlates with improved rat renal isograft viability and survival in kidneys harvested from non-heart-beating donors. 1179 32

Podocyte injury is a central mechanism in the pathogenesis of proteinuria. Prostaglandin E2 (PGE2) has been suggested to protect podocytes from cellular injury. Here we investigated whether PGE2-induced gene expression accounts for the protective role of PGE2 in podocytes. Using a suppressive-subtractive hybridization method, we isolated a differentially expressed clone that was identified as Stra13, a recently described retinoic acid-inducible gene. PGE2, forskolin, and retinoic acid induced a time-dependent up-regulation of Stra13 mRNA and protein expression in podocytes. To test the function of Stra13 in podocytes, Stra13 was overexpressed by using retroviral gene transfer. Compared with control cells, cells overexpressing Stra13 showed markedly reduced NADPH-dependent superoxid anion generation. Furthermore, expression of heme oxygenase 1 (HO-1) was increased in podocytes overexpressing Stra13. HO-1 plays an important protective role in the defense against reactive oxygen species (ROS). After stimulation with exogenous ROS, Stra13-overexpressing podocytes were more resistant to oxidative stress than were control cells. Our data indicate that Stra13 may play an important protective role against oxidative stress in podocytes. ROS are involved in the pathogenesis of glomerular inflammation in several forms of glomerulonephritis. Therefore, knowledge about protective mechanisms may provide insight into new therapeutic strategies for glomerulopathies.
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PMID:Stra13, a prostaglandin E2-induced gene, regulates the cellular redox state of podocytes. 1259 85

Inflammatory infiltrates can modify (lipo)proteins via hypochlorous acid/hypochlorite (HOCl/OCl(-)) an oxidant formed by the myeloperoxidase-H(2)O(2)-halide system. These oxidatively modified proteins emerge in tubuli in some proteinuric and interstitial diseases. Human proximal tubular cells (HK-2) were used to confirm the hypothesis of detrimental and differential impact of HOCl-modified low density lipoprotein (HOCl-LDL), an in vivo occurring lipoprotein modification exerting proatherogenic and proinflammatory capacity. HOCl-LDL showed dose-dependent antiproliferative effects in HK-2 cells. Small dedicated cDNA macroarrays were used to identify differentially regulated genes. A rapid increase in the expression of genes involved in reactive oxygen species metabolism and cell stress, eg, heme oxygenase-1, thioredoxin reductase, cytochrome b5 reductase, Gadd 153, amino acid transporter E16, and HSP70 was found after HOCl-LDL treatment of HK-2 cells. In parallel, genes involved in tissue remodeling and inflammation eg, CTGF, VCAM-1, IL-1beta, MMP7, and VEGF were up-regulated. Quantitative RT-PCR verified differential expression of a subset of these genes in microdissected tubulointerstitia from patients with acute tubular damage, progressive proteinuric renal disease, and membranous glomerulonephritis (with declining renal function), but not in stable patients with proteinuria caused by minimal change disease. The demonstration of selective up-regulation of a subgroup of genes if proteinuria is accompanied by the presence of HOCl-modified (lipo)proteins support the potential pathophysiological role of the myeloperoxidase-H(2)O(2)-halide system and HOCl-LDL in renal disease.
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PMID:Influence of native and hypochlorite-modified low-density lipoprotein on gene expression in human proximal tubular epithelium. 1516 51

To clarify the patterns of heme oxygenase-1 (HO-1) production within the human kidney, we examined HO-1 mRNA expression in various renal diseases and compared the patterns with those of HO-1 protein expression and these data with the clinical features. The degrees of hematuria and proteinuria and the levels of urinary N-acetyl-beta-D-glucosaminidase (NAG), beta(2)-microglobulin (beta(2)-mg), and creatinine were determined. In situ hybridization and immunohistochemical studies were performed to evaluate HO-1 expression. HO-1 mRNA was detectable within tubular, glomerular, and Bowman's epithelial cells and infiltrating macrophages. Within the proximal tubuli, there was a correlation between expression of HO-1 protein and mRNA, but the intensity of HO-1 mRNA expression was much less than expected from the levels of protein. In contrast, both HO-1 protein and mRNA were expressed at significant levels within distal tubuli. Furthermore, there was no correlation with both expressions within distal tubuli. HO-1 mRNA expression within tubular, glomerular, and Bowman's epithelial cells tended to be more intense with greater degrees of proteinuria. However, there was little correlation between the intensity of HO-1 mRNA expression and the degree of hematuria, NAG, and beta(2)-mg. HO-1 plays important roles in maintaining renal functions by protecting renal epithelial cells from glomerular proteinuria, which can become a cause of oxidative stress. Furthermore, from the different expression pattern of HO-1 gene between within the proximal tubuli and within the distal tubuli, renal expression of HO-1 is regulated in a segment-specific manner, with HO-1 thereby playing distinct roles in different segments of the nephron to maintain renal functions.
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PMID:Glomerular proteinuria induces heme oxygenase-1 gene expression within renal epithelial cells. 1618 91

Clinical studies have demonstrated that some antihypertensive agents provide renoprotection independent of BP lowering. Recent in vitro and in vivo studies evaluated the mechanisms involved in this protection. First, the in vitro effects of several angiotensin II type 1 receptor blockers (ARB), calcium channel blockers (CCB), and beta blockers (BB) on various mediators were compared: Formation of pentosidine (an advanced glycation end product), hydroxyl radical-induced formation of o-tyrosine, and transition metals-induced oxidation of ascorbic acid (the Fenton reaction). All of the six tested ARB but neither the six CCB nor the nine BB inhibited pentosidine formation. ARB, as well as BB but not CCB, inhibited hydroxyl radicals-mediated o-tyrosine formation. ARB but neither BB nor CCB inhibited efficiently transition metals-catalyzed oxidation of ascorbic acid. Second, the in vivo consequences for the kidney of these various in vitro effects were evaluated. Hypertensive, type 2 diabetic rats with nephropathy, SHR/NDmcr-cp, were given for 20 wk either olmesartan (ARB) or nifedipine (CCB), or atenolol (BB). Despite similar BP reduction, only ARB significantly reduced proteinuria and prevented glomerular and tubulointerstitial damage (mesangial activation, podocyte injury, tubulointerstitial injury, and inflammatory cell infiltration). It is interesting that only ARB prevented abnormal iron deposition in the interstitium, corrected chronic hypoxia, reduced expressions of heme oxygenase and p47phox (a subunit of NADPHoxidase), and inhibited pentosidine formation (which correlates well with proteinuria). These observations confirm unique renoprotective properties of ARB, independent of BP lowering but related to decreased oxidative stress (hydroxyl radicals scavenging and inhibition of the Fenton reaction), correction of chronic hypoxia, and inhibition of advanced glycation end product formation and of abnormal iron deposition. These benefits of ARB may contribute to the renoprotection observed beyond BP lowering.
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PMID:Renoprotective properties of angiotensin receptor blockers beyond blood pressure lowering. 1623 4

Proteinuria contributes to chronic kidney disease by stimulating renal tubular epithelial cells to produce cytokines such as monocyte chemoattractant protein-1 (MCP-1). The present study determined whether cellular overexpression of heme oxygenase-1 (HO-1) can influence albumin-stimulated MCP-1 production. In response to bovine serum albumin, NRK-52E cells constitutively overexpressing HO-1 (HO-1 OE cells) exhibit less induction of MCP-1 mRNA and less production of MCP-1 protein compared with similarly treated, control NRK-52E cells (CON cells). In wild-type NRK-52E cells, and under these conditions, we demonstrate that the induction of MCP-1 is critically dependent on intact NF-kappaB binding sites in the MCP-1 promoter. In response to albumin, CON cells exhibit activation of NF-kappaB, and this is reduced in HO-1 OE cells. Albumin also activates ERK1/2 and increases ERK activity, both of which are exaggerated in HO-1 OE cells. Studies with an inhibitor of MAPK/ERK kinase (U0126) demonstrate that the inhibitory effects of U0126 on MCP-1 production are attenuated in HO-1 OE cells. We conclude that HO-1 overexpression in the proximal tubule reduces MCP-1 production in response to albumin, and this occurs, at least in part, by inhibiting an ERK-dependent, NF-kappaB-dependent pathway at a site that is distal to the activation of ERK. These findings suggest that the induction of HO-1 in the proximal tubule, as occurs in chronic kidney disease, may be a countervailing response that reduces albumin-stimulated production of cytokines such as MCP-1.
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PMID:Renal upregulation of HO-1 reduces albumin-driven MCP-1 production: implications for chronic kidney disease. 1696 90

It has been suggested that oxidative stress is involved in d-serine-induced nephrotoxicity. The purpose of this study was to assess if oxidative stress is involved in this experimental model using several approaches including (a) the determination of several markers of oxidative stress and the activity of some antioxidant enzymes in kidney and (b) the use of compounds with antioxidant or prooxidant effects. Rats were sacrificed at several periods of time (from 3 to 24h) after a single i.p. injection of d-serine (400mg/kg). Control rats were injected with l-serine (400mg/kg) and sacrificed 24h after. The following markers were used to assess the temporal aspects of renal damage: (a) urea nitrogen (BUN) and creatinine in blood serum, (b) kidney injury molecule (KIM-1) mRNA levels, and (c) tubular necrotic damage. In addition, creatinine clearance, proteinuria, and urinary excretion of N-acetyl-beta-d-glucosaminidase (NAG) were measured 24h after d-serine injection. Protein carbonyl content, malondialdehyde (MDA), 4-hydroxy-2-nonenal (4-HNE), fluorescent products of lipid peroxidation, reactive oxygen species (ROS), glutathione (GSH) content, and heme oxygenase-1 (HO-1) expression were measured as markers of oxidative stress in the kidney. Additional experiments were performed using the following compounds with antioxidant or pro-oxidant effects before d-serine injection: (a) alpha-phenyl-tert-butyl-nitrone (PBN), a spin trapping agent; (b) 5,10,15,20-tetrakis (4-sulfonatophenyl) porphyrinato iron(III) (FeTPPS), a soluble complex able to metabolize peroxynitrite; (c) aminotriazole (ATZ), a catalase (CAT) inhibitor; (d) stannous chloride (SnCl(2)), an HO-1 inductor; (e) tin mesoporphyrin (SnMP), an HO inhibitor. In the time-course study, serum creatinine and BUN increased significantly on 15-24 and 20-24h, respectively, and KIM-1 mRNA levels increased significantly on 6-24h. Histological analyses revealed tubular necrosis at 12h. The activity of antioxidant enzymes catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase remained unchanged at all times studied. Protein carbonyl content, MDA, 4-HNE, and ROS remained unchanged at all time-points studied. GSH content decreased transiently on 9 and 12h. Interestingly, fluorescent products of lipid peroxidation decreased significantly on 3-24h. HO-1 expression was undetectable by Western blot and the immunohistochemistry studies revealed that the intensity of HO-1 staining was weak. The administration of PBN, FeTPPS, ATZ, SnCl(2), and SnMP did not prevent or enhance renal damage induced by d-serine. Our data taken as a whole suggest that oxidative stress is not involved in the early phase of the nephrotoxicity induced by d-serine.
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PMID:Evaluation of oxidative stress in D-serine induced nephrotoxicity. 1711 13

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