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

The p38 mitogen-activated protein kinase (MAPK) pathway is a pro-inflammatory signal transduction pathway. The aim of this study was to examine the role of this pathway in acute renal inflammation. Immunostaining localized components of the p38 MAPK pathway (p38alpha, p-p38, p-ATF-2) in normal glomeruli, to podocytes, and occasional endothelial cells. This study identified an eightfold increase in glomerular activation of p38 MAPK (phosphorylated p38, p-p38) within 3 h of the induction of rat anti-glomerular basement membrane (GBM) glomerulonephritis and localized p-p38 and p-ATF-2 to infiltrating neutrophils, with increased staining of podocytes and endothelial cells. The relevance of these findings to human acute inflammatory renal disease was determined by examination of biopsy specimens. In patients with post-infectious glomerulonephritis, there was an increased number of positive p-p38 glomerular cells, including p-p38 staining of infiltrating neutrophils, compared with normal human kidney. In rats, administration of a specific p38 MAPK inhibitor, NPC 31145, before induction of anti-GBM disease prevented a loss of renal function and substantially reduced proteinuria. The reduction in renal injury was attributed to a 55% reduction in glomerular neutrophil infiltration and a 68% reduction in platelet accumulation. This was associated with an abrogation of glomerular P-selectin immunostaining and inhibition of glomerular P-selectin gene expression. In summary, this study has localized the components of the p38 MAPK pathway to cells in normal and diseased rat and human kidney and identified a number of important mechanisms by which signaling through the p38 MAPK pathway induces inflammatory renal disease. Blockade of the p38 pathway may be a novel therapeutic strategy for the treatment of acute renal inflammation.
 ...
PMID:Blockade of p38alpha MAPK ameliorates acute inflammatory renal injury in rat anti-GBM glomerulonephritis. 1253 34

Investigated was the effect of high albumin concentrations on proximal tubular cell expression of fractalkine. Human proximal tubular cells (HK-2) were incubated with human serum albumin (HSA), which induced a dose-dependent increase in fractalkine mRNA associated with increased levels of both membrane-bound and soluble forms of the protein. To evaluate the role of nuclear factor kappaB (NF-kappaB) activation in HSA-induced fractalkine mRNA, HK-2 cells were infected with a recombinant adenovirus encoding the natural inhibitor of NF-kappaB, IkBalpha; a 43% reduction of fractalkine mRNA levels resulted. Similarly, when cells were infected with the recombinant adenovirus expressing dominant negative mutant of the IkB kinase 2, a 55% inhibition of fractalkine mRNA was achieved. p38 mitogen-activated protein kinase was activated by HSA and was involved in NF-kappaB-dependent transcription of fractalkine. In kidneys of mice with bovine serum albumin overload proteinuria, fractalkine mRNA levels were 2.3-fold greater than those of controls. Fractalkine expression was also induced in tubular epithelial cells in this model. Anti-CXCR1 antibody treatment limited interstitial accumulation of mononuclear cells. Protein overload is a promoter of fractalkine gene induction mediated by NF-kappaB and p38 activation in proximal tubular cells. Fractalkine might contribute to direct mononuclear cells into peritubular interstitium and enhance their adhesion property, which in turn would favor inflammation and disease progression.
 ...
PMID:Protein overload induces fractalkine upregulation in proximal tubular cells through nuclear factor kappaB- and p38 mitogen-activated protein kinase-dependent pathways. 1451 21

Activation of the p38 mitogen-activated protein kinase (MAPK) signal transduction pathway plays an important role in the inflammatory response. It was postulated that p38 MAPK is important in the pathogenesis of human glomerulonephritis and contributes to the development of renal injury. p38 MAPK activation was examined by immunodetection for dual phosphorylated p38 (p-p38) in normal human kidney and 77 renal biopsy specimens encompassing a wide spectrum of glomerulonephritides. In normal kidney, p-p38 immunostaining was restricted to the nuclei of a small number of podocytes, parietal epithelial cells, and tubular cells. There was a dramatic increase in the number of p-p38-positive cells in glomeruli and tubules in nonproliferative and proliferative glomerulonephritis and a substantial increase in the number of interstitial p-p38-positive cells in proliferative glomerulonephritis. Double immunostaining identified p38 activation in intrinsic renal cells (podocytes and endothelial and tubular cells), infiltrating macrophage and neutrophils, and myofibroblasts. Renal failure correlated with the number of p-p38-positive glomerular, tubular, and interstitial cells. Proteinuria correlated with the number of p-p38-positive tubular and interstitial cells and the number of p-p38-positive podocytes in nonproliferative glomerulonephritis. Furthermore, glomerular p38 activation correlated with segmental proliferative and necrotic lesions, and interstitial p38 activation correlated with the degree of interstitial inflammation. In conclusion, activation of p38 MAPK in intrinsic renal cells and infiltrating leukocytes correlated with renal dysfunction and histopathology, suggesting an important pathogenic role for p38 MAPK activation in human glomerulonephritis.
 ...
PMID:p38 Mitogen-activated protein kinase activation and cell localization in human glomerulonephritis: correlation with renal injury. 1474 79

Activation of p38 mitogen-activated protein kinase (MAPK) is known to be important in cytokine production and cell survival in inflammation. This study examined the effect of inhibiting p38 MAPK after onset of renal injury in an experimental model of crescentic glomerulonephritis. Furthermore, this study investigated whether p38 MAPK inhibition would cause widespread suppression of the cytokine network in vivo or uncontrolled apoptosis. In the in vivo studies, daily treatment with a p38 MAPKalpha/beta inhibitor was started 1 h (early treatment study) or 4 d (late treatment study) after induction of nephrotoxic nephritis in Wistar Kyoto rats. The treated rats remained healthy with normal weight gain during the study. Both early and late treatment with p38 MAPK inhibitor reduced renal monocyte chemoattractant protein-1 (MCP-1) levels, the number of glomerular macrophages, the severity of tissue injury, and proteinuria compared with the vehicle group. Unexpected, treatment with p38 MAPK inhibitor did not suppress renal levels of IL-1beta or IL-6. In the in vitro study, the p38 MAPKalpha/beta inhibitor reduced production of MCP-1 and IL-6 by TNF-alpha-or IL-1beta-stimulated mesangial cells without any effect on cell viability or apoptosis. In conclusion, p38 MAPK inhibition is effective in reducing the severity of crescentic glomerulonephritis even when treatment is started after onset of disease. The therapeutic effect is associated with selective suppression of MCP-1, without widespread suppression of cytokine production or increased apoptosis. Therefore, p38 MAPK therapeutic blockade is a promising strategy in the treatment of antibody-mediated glomerulonephritis.
 ...
PMID:Inhibition of p38 mitogen-activated protein kinase is effective in the treatment of experimental crescentic glomerulonephritis and suppresses monocyte chemoattractant protein-1 but not IL-1beta or IL-6. 1731 28

The occurrence and extent of apoptosis in the kidneys of patients with diabetic nephropathy is largely unknown. We evaluated apoptosis in renal biopsies obtained from patients with early or advanced type II diabetic nephropathy. Apoptosis was about 6- and 3-fold higher, respectively, in glomeruli and tubules in kidneys of patients with early nephropathy than in the normal kidney and this was not further increased in advanced diabetic nephropathy. Glomerular apoptosis was related directly to hemoglobin A1(c) and systolic blood pressure, whereas tubular cell apoptosis correlated to diabetes duration and low-density lipoprotein-cholesterol. Fas, Fas ligand, and p38 mitogen-activated protein kinase expressions were enhanced in glomeruli and tubules; however, this did not correlate with apoptosis. In patients with proteinuria, apoptosis was associated with the subsequent loss of kidney function. When these parameters were subjected to multivariate analysis, only glomerular apoptosis retained a significant independent predictive value. Our findings suggest that apoptosis might be a clinically relevant mechanism of glomerular and tubular cell loss in proteinuric type II diabetic patients.
 ...
PMID:Apoptosis in the kidneys of patients with type II diabetic nephropathy. 1862

An inverse relationship exists between kallistatin levels and salt-induced oxidative stress in Dahl-salt sensitive rats. We further investigated the role of kallistatin in inhibiting inflammation and fibrosis through antioxidative stress in Dahl-salt sensitive rats and cultured renal cells. High-salt intake in Dahl-salt sensitive rats induced elevation of thiobarbituric acid reactive substances (an indicator of lipid peroxidation), malondialdehyde levels, reduced nicotinamide-adenine dinucleotide phosphate oxidase activity, and superoxide formation, whereas kallistatin gene delivery significantly reduced these oxidative stress parameters. Kallistatin treatment improved renal function and reduced kidney damage as evidenced by diminished proteinuria and serum urea nitrogen levels, glomerular sclerosis, tubular damage, and protein cast formation. Kallistatin significantly decreased interstitial monocyte-macrophage infiltration and the expression of tumor necrosis factor-alpha, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1. Kallistain also reduced collagen fraction volume and the deposition and expression of collagen types I and III. Renal protection by kallistatin was associated with increased NO levels and endothelial NO synthase expression and decreased p38 mitogen-activated protein kinase, extracellular signal-regulated kinase phosphorylation, and transforming growth factor-beta1 expression. Moreover, kallistatin attenuated tumor necrosis factor-alpha-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression via inhibition of reactive oxygen species formation and p38 mitogen-activated protein kinase and nuclear factor-kappaB activation in cultured proximal tubular cells. Kallistatin inhibited fibronectin and collagen expression by suppressing angiotensin II-induced reactive oxygen species generation and transforming growth factor-beta1 expression in cultured mesangial cells. These combined findings reveal that kallistatin is a novel antioxidant, which prevents salt-induced kidney injury, inflammation, and fibrosis by inhibiting reactive oxygen species-induced proinflammatory cytokine and transforming growth factor-beta1 expression.
 ...
PMID:Salutary effect of kallistatin in salt-induced renal injury, inflammation, and fibrosis via antioxidative stress. 1839 Oct 98

Extracts of Tripterygium wilfordii Hook F have been used to treat glomerulonephritis for more than 30 years in China with dramatic antiproteinuric effects. Triptolide, a diterpene triepoxide, is one of the major active components of these extracts. To clarify its antiproteinuric effects we induced podocyte injury by puromycin aminonucleoside. Triptolide effectively reduced the proteinuria induced by puromycin in nephrotic rats without reducing the glomerular filtration rate. The antiproteinuric effect was associated with improvement in the foot process effacement, a decrease in the podocyte injury marker desmin as well as the restoration of nephrin and podocin expression and distribution. In cultured mouse podocytes triptolide pretreatment prevented the puromycin-induced disruption of the actin cytoskeleton and microfilament-associated synaptopodin while protecting nephrin and podocin expression. Triptolide suppressed reactive oxygen species generation and p38 mitogen-activated protein kinase activation while restoring RhoA signaling activity. These results show that triptolide ameliorates puromycin aminonucleoside-mediated podocyte injury in vivo and in vitro.
 ...
PMID:Triptolide protects podocytes from puromycin aminonucleoside induced injury in vivo and in vitro. 1850 22

In diabetic nephropathy, transforming growth factor beta1 (TGFbeta1) is related to p38 mitogen-activated protein kinase (MAPK) that induces production of fibronectin in mesangial cells. We investigated the effects of alpha-lipoic acid (ALA), a potent antioxidant, on proteinuria and TGFbeta1-p38 MAPK-fibronectin pathway in diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. After ALA treatment for 5 weeks in OLETF rats at 30 weeks of age, plasma malondialdehyde, urinary protein excretion, renal cortical TGFbeta1, and fibronectin protein levels were decreased; and urinary protein excretion was positively correlated with renal cortical TGFbeta1 and fibronectin protein levels. Phospho-form but not total-form levels as well as fold activations of each protein consisting of p38 MAPK pathway were also attenuated. These results suggest that ALA ameliorates proteinuria by attenuating expressions of TGFbeta1 and fibronectin proteins, and these favorable effects are related to inhibition of phosphorylating activation of p38 MAPK pathway in renal cortex of OLETF rats.
 ...
PMID:Effects of alpha-lipoic acid on transforming growth factor beta1-p38 mitogen-activated protein kinase-fibronectin pathway in diabetic nephropathy. 1937 83

Proteinuria is a well-established exacerbating factor in chronic kidney disease. Although the mechanisms of albumin-induced tubulointerstitial damage have been extensively studied, the influence of mycophenolic acid (MPA) on tubular epithelial cells has not been sufficiently elucidated. MPA, the active metabolite of mycophenolate mofetil, is a potent, non-competitive, and reversible inhibitor of inosine-5'-monophosphate dehydrogenase, the rate-limiting enzyme for de novo purine synthesis. Monocyte chemoattractant protein 1 (MCP-1) is a 76-amino-acid chemokine thought to be the major chemotactic factor for monocytes. MCP-1 is found in macrophage-rich areas of atherosclerotic lesions. However, the mechanisms regulating MCP-1 expression by MPA in renal tubular epithelial cells were still unclear. In this study, the inhibitory effect of MPA on MCP-1 expression by albumin-induced renal tubular epithelial cells was investigated, and the roles of p38 mitogen-activated protein kinase (p38 MAPK) pathway were explored. MPA attenuated albumin-induced expression of MCP-1 mRNA and protein. The experiment suggested that MPA actively inhibited protein of MCP-1. The inhibitory effect of MPA on MCP-1 expression was mediated by the sequential attenuation of p38 MAPK expression. These inhibitory effects were partially inhibited by SB203580, a specific inhibitor of p38 MAPK. Taken together, these results suggest that the negative modulation of MCP-1 by MPA is partly dependent on p38 MAPK pathway.
 ...
PMID:Mycophenolic acid inhibits albumin-induced MCP-1 expression in renal tubular epithelial cells through the p38 MAPK pathway. 1957 79

Membranous nephropathy is a major cause of nephrotic syndrome in adults where podocyte injuries were found to mediate the development of proteinuria. Triptolide, a major active component of Tripterygium wilfordii Hook F, has potent immunosuppressive, anti-inflammatory and antiproteinuric effects. To study its antiproteinuric properties, we established an experimental rat model of passive Heymann nephritis and a C5b-9 injury model of podocytes in vitro. Treatment or pretreatment with triptolide markedly reduced established proteinuria as well as the titer of circulating rat anti-rabbit IgG antibodies in these nephritic rats, accompanied by a reduction in glomerular C5b-9 deposits. Expression of desmin, a marker of podocyte injury, diminished after triptolide treatment, whereas quantitative analysis of mean foot process width showed that effacement of foot processes was substantially reversed. In in vitro studies we found that triptolide deactivated NADPH oxidase, suppressed reactive oxygen species generation and p38 mitogen-activated protein kinase, and restored RhoA signaling activity. Triptolide did not interfere with the formation of C5b-9 on the membrane of podocytes. Thus, triptolide reduces established heavy proteinuria and podocyte injuries in rats with passive Heymann nephritis, and protects podocytes from C5b-9-mediated injury.
 ...
PMID:Triptolide reduces proteinuria in experimental membranous nephropathy and protects against C5b-9-induced podocyte injury in vitro. 2037 80


1 2 3 Next >>