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)

Glomerular epithelial protein 1 (GLEPP1) is a podocyte receptor membrane protein tyrosine phosphatase located on the apical cell membrane of visceral glomerular epithelial cell and foot processes. This receptor plays a role in regulating the structure and function of podocyte foot process. To better understand the utility of GLEPP1 as a marker of glomerular injury, the amount and distribution of GLEPP1 protein and mRNA were examined by immunohistochemistry, Western blot and RNase protection assay in a model of podocyte injury in the rat. Puromycin aminonucleoside nephrosis was induced by single intraperitoneal injection of puromycin aminonucleoside (PAN, 20 mg/100g BW). Tissues were analyzed at 0, 5, 7, 11, 21, 45, 80 and 126 days after PAN injection so as to include both the acute phase of proteinuria associated with foot process effacement (days 5-11) and the chronic phase of proteinuria associated with glomerulosclerosis (days 45-126). At day 5, GLEPP1 protein and mRNA were reduced from the normal range (265.2 +/- 79.6 x 10(6) moles/glomerulus and 100%) to 15% of normal (41.8 +/- 4.8 x 10(6) moles/glomerulus, p < 0.005). This occurred in association with an increase in urinary protein content from 1.8 +/- 1 to 99.0 +/- 61 mg/day (p < 0.001). In contrast, podocalyxin did not change significantly at this time. By day 11, GLEPP1 protein and mRNA had begun to return towards baseline. By day 45-126, at a time when glomerular scarring was present, GLEPP1 was absent from glomerulosclerotic areas although the total glomerular content of GLEPP1 was not different from normal. We conclude that GLEPP1 expression, unlike podocalyxin, reflects podocyte injury induced by PAN. GLEPP1 expression may be a useful marker of podocyte injury.
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PMID:GLEPP1 receptor tyrosine phosphatase (Ptpro) in rat PAN nephrosis. A marker of acute podocyte injury. 1196 7

Proteinuria is a poorly understood feature of many acquired renal diseases. Recent studies concerning congenital nephrotic syndromes and findings in genetically modified mice have demonstrated that podocyte molecules make a pivotal contribution to the maintenance of the selective filtration barrier of the normal glomerulus. However, it is unclear what role podocyte molecules play in proteinuria of acquired renal diseases. This study investigated the mRNA and protein expression of several podocyte-associated molecules in acquired renal diseases. Forty-eight patients with various renal diseases were studied, including minimal change nephropathy, focal segmental glomerulosclerosis, IgA nephropathy, lupus nephritis, and diabetic nephropathy, together with 13 kidneys with normal glomerular function. Protein levels of nephrin, podocin, CD2-associated protein, and podocalyxin were investigated using quantitative immunohistochemical assays. Real-time PCR was used to determine the mRNA levels of nephrin, podocin, and podoplanin in microdissected glomeruli. The obtained molecular data were related to electron microscopic ultrastructural changes, in particular foot process width, and to clinical parameters. In most acquired renal diseases, except in IgA nephropathy, a marked reduction was observed at the protein levels of nephrin, podocin, and podocalyxin, whereas an increase of the glomerular mRNA levels of nephrin, podocin, and podoplanin was found, compared with controls. The mean width of the podocyte foot processes was inversely correlated with the protein levels of nephrin (r = -0.443, P < 0.05), whereas it was positively correlated with podoplanin mRNA levels (r = 0.468, P < 0.05) and proteinuria (r = 0.585, P = 0.001). In the diseases studied, the decrease of slit diaphragm proteins was related to the effacement of foot processes and coincided with a rise of the levels of the corresponding mRNA transcripts. This suggests that the alterations in the expression of podocyte-associated molecules represent a compensatory reaction of the podocyte that results from damage associated with proteinuria.
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PMID:Expression of podocyte-associated molecules in acquired human kidney diseases. 1287 60

Renal failure is a frequent and costly complication of many chronic diseases, including diabetes and hypertension. One common feature of renal failure is glomerulosclerosis, the pathobiology of which is unclear. To help elucidate this, we generated a mouse strain carrying the missense mutation Wt1 R394W, which predisposes humans to glomerulosclerosis and early-onset renal failure (Denys-Drash syndrome [DDS]). Kidney development was normal in Wt1(+/R394W) heterozygotes. However, by 4 months of age 100% of male heterozygotes displayed proteinuria and glomerulosclerosis characteristic of DDS patients. This phenotype was observed in an MF1 background but not in a mixed B6/129 background, suggestive of the action of a strain-specific modifying gene(s). WT1 encodes a nuclear transcription factor, and the R394W mutation is known to impair this function. Therefore, to investigate the mechanism of Wt1 R394W-induced renal failure, the expression of genes whose deletion leads to glomerulosclerosis (NPHS1, NPHS2, and CD2AP) was quantitated. In mutant kidneys, NPHS1 and NPHS2 were only moderately downregulated (25 to 30%) at birth but not at 2 or 4 months. Expression of CD2AP was not changed at birth but was significantly upregulated at 2 and 4 months. Podocalyxin was downregulated by 20% in newborn kidneys but not in kidneys at later ages. Two other genes implicated in glomerulosclerosis, TGFB1 and IGF1, were upregulated at 2 months and at 2 and 4 months, respectively. It is not clear whether the significant alterations in gene expression are a cause or a consequence of the disease process. However, the data do suggest that Wt1 R394W-induced glomerulosclerosis may be independent of downregulation of the genes for NPHS1, NPHS2, CD2AP, and podocalyxin and may involve other genes yet to be implicated in renal failure. The Wt1(R394W) mouse recapitulates the pathology and disease progression observed in patients carrying the same mutation, and the mutation is completely penetrant in male animals. Thus, it will be a powerful and biologically relevant model for investigating the pathobiology of the earliest events in glomerulosclerosis.
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PMID:The Wt1+/R394W mouse displays glomerulosclerosis and early-onset renal failure characteristic of human Denys-Drash syndrome. 1550 92

This study aimed to generate a mouse model of acquired glomerular sclerosis. A model system that allows induction of podocyte injury in a manner in which onset and severity can be controlled was designed. A transgenic mouse strain (NEP25) that expresses human CD25 selectively in podocytes was first generated. Injection of anti-Tac (Fv)-PE38 (LMB2), an immunotoxin with specific binding to human CD25, induced progressive nonselective proteinuria, ascites, and edema in NEP25 mice. Podocytes showed foot process effacement, vacuolar degeneration, detachment and downregulation of synaptopodin, WT-1, nephrin, and podocalyxin. Mesangial cells showed matrix expansion, increased collagen, mesangiolysis, and, later, sclerosis. Parietal epithelial cells showed vacuolar degeneration and proliferation, whereas endothelial cells were swollen. The severity of the glomerular injury was LMB2 dose dependent. With 1.25 ng/g body wt or more, NEP25 mice developed progressive glomerular damage and died within 2 wk. With 0.625 ng/g body wt of LMB2, NEP25 mice survived >4 wk and developed focal segmental glomerular sclerosis. Thus, the study has established a mouse model of acquired progressive glomerular sclerosis in which onset and severity can be preprogrammed by experimental maneuvers.
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PMID:Genetic engineering of glomerular sclerosis in the mouse via control of onset and severity of podocyte-specific injury. 1575 46

Whether podocyte depletion could cause the glomerulosclerosis of aging in Fischer 344 rats at ages 2, 6, 17, and 24 mo was evaluated. Ad libitum-fed rats developed proteinuria and glomerulosclerosis by 24 mo, whereas calorie-restricted rats did not. No evidence of age-associated progressive linear loss of podocytes from glomeruli was found. Rather, ad libitum-fed rats developed glomerular enlargement over time. To accommodate the increased glomerular volume, podocytes principally underwent hypertrophy, whereas other glomerular cells underwent hyperplasia. Stages of hypertrophy through which podocytes pass en route to podocyte loss and glomerulosclerosis were identified: Stage 1, normal podocyte; stage 2, nonstressed podocyte hypertrophy; stage 3, "adaptive" podocyte hypertrophy manifest by changes in synthesis of structural components (e.g., desmin) but maintenance of normal function; stage 4, "decompensated" podocyte hypertrophy relative to total glomerular volume manifest by reduced production of key machinery necessary for normal podocyte function (e.g., Wilms' tumor 1 protein [WT1], transcription factor pod1, nephrin, glomerular epithelial protein 1, podocalyxin, vascular endothelial growth factor, and alpha5 type IV collagen) and associated with widened foot processes and decreased filter efficiency (proteinuria); and stage 5, podocyte numbers decrease in association with focal segmental glomerulosclerosis. In contrast, in calorie-restricted rats, glomerular enlargement was minor, significant podocyte hypertrophy did not occur, podocyte machinery was unchanged, there was no proteinuria, and glomerulosclerosis did not develop. Glomerular enlargement therefore was associated with podocyte hypertrophy rather than hyperplasia. Hypertrophy above a certain threshold was associated with podocyte stress and then failure, culminating in reduced podocyte numbers in sclerotic glomeruli. This process could be prevented by calorie restriction.
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PMID:Podocyte hypertrophy, "adaptation," and "decompensation" associated with glomerular enlargement and glomerulosclerosis in the aging rat: prevention by calorie restriction. 1614 37

The glomerular podocyte plays a key role in maintaining the integrity of the glomerular filtration barrier. This function may be regulated by activation of cell surface G protein-coupled receptors (GPCR). Studies suggest that podocytes express GPCR that are implicated in the pathogenesis of glomerular diseases. Common to these GPCR systems is activation of phospholipase C through the Gq alpha-subunit (Galpha q). For investigating the role of Galpha q-coupled signaling pathways in promoting renal injury in podocytes, a constitutively active Galpha q subunit (Galpha qQ > L) was expressed in glomerular podocytes using the mouse nephrin promoter. Transgenic (TG) mice demonstrated albuminuria as well as a decrease in both kidney mass and nephron number. By light microscopy, a portion of the TG mice had glomerular abnormalities, including focal to diffuse hypercellularity and segmental sclerosis. Consistent with injury-promoting effects of Galpha qQ > L, there was a significant reduction in podocalyxin mRNA as well as nephrin mRNA and protein levels in glomeruli from TG mice compared with non-TG controls. Expression of the transgene also seemed to increase susceptibility to glomerular injury, because treatment with puromycin aminonucleoside enhanced proteinuria in TG mice compared with non-TG littermate controls (4.2 +/- 1.0 [TG] versus 1.6 +/- 0.3 [non-TG] mg/24 h; P = 0.0161). Thus, activation of Galpha q in glomerular podocytes caused alterations in glomerular histomorphology, albuminuria, decreased nephron mass, and reduced glomerular expression of both nephrin and podocalyxin as well as enhanced susceptibility to glomerular damage induced by puromycin aminonucleoside. It is speculated that Galpha q-coupled signaling cascades may be important effector pathways mediating renal injury.
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PMID:Activation of Galpha q-coupled signaling pathways in glomerular podocytes promotes renal injury. 1626 59

CD2AP, alpha-actinin-4 and podocalyxin are thought to play an important role in the structure and function of glomerular podocytes, therefore we intended to evaluate quantitatively, using computer image analysis system, the immunoexpression of these proteins in renal biopsy specimens in glomerulopathies presented with nephrotic syndrome: minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS) and nephropathy IgA (IgAN). As a control 10 biopsy specimens of the kidneys removed because of trauma were used. In normal kidneys CD2AP, alpha-actinin-4, and podocalyxin showed intense staining in podocytes along the capillary walls of the glomeruli. The intensity of immunoexpression of CD2AP and alpha-actinin-4 in renal tissue in patients with MCD, FSGS, and IgAN was similar to normal controls, but the distribution of these proteins was more granular in glomeruli of diseased kidney. The immunostaining of podocalyxin was weaker in podocytes in patients with FSGS as compared with normal glomeruli. The immunostaining of podocalyxin was not significantly altered in MCD and IgAN. The immunostaining of CD2AP and alpha-actinin-4 did not correlate with the intensity of proteinuria in patients with MCD, FSGS and IgAN, whilst in FSGS patients the significant correlation was found between the glomerular immunostaining of podocalyxin and proteinuria. In conclusion, revealed in our study diminished immunoexpression of podocalyxin and significant correlation with the level of proteinuria in FSGS patients suggests a possible role of this sialoprotein in the alteration of the glomerular filtration barrier in this disease.
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PMID:Immunoexpression of podocyte-associated proteins in acquired human glomerulopathies with nephrotic syndrome. 1673 78

Idiopathic nephrotic syndrome in children may be complicated by resistance to steroids with constant proteinuria in diffuse mesangial proliferation (DMP) and focal segmental glomerulosclerosis (FSGS). In our observation, sometimes in children with steroid-resistant nephrotic syndrome, the presence of immature renal glomeruli can be detected (hypercellularity and presence of a constant layer of cubical epithelial cells on the surface of glomerular tufts, without sclerosis, resembling M-stage of glomerulo-genesis). The aim of this study was immunohistochemical analysis of the podo-cyte-associated proteins, particularly ezrin, podocalyxin, synaptopodin and nephrin in glomeruli with and without signs of immaturity in children. In DMP with signs of immaturity podo-cytes situated in the central region of the glomerulus were immunohistochemically negative. The positive reaction was observed exclusively in the most superficial continuous 'layer' of podo-cytes. The unfavourable clinical course of nephrotic syndrome with signs of glomerular immaturity may be a consequence of decreased immunohistochemical expression of cytoskeleton-specific proteins.
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PMID:[Immunohistochemical analysis of podocytopathy with immature glomeruli and glomerulosclerosis in children with nephrotic syndrome]. 1689 1

Urinary exosomes are excreted from all nephron segments and may serve as biomarkers for classifying renal diseases. Isolation of urinary exosomes by the established ultracentrifugation method has some limitations for use in a clinical laboratory. We sought a rapid and simple way to obtain urinary exosomes. We used a commercially available nanomembrane concentrator to enrich exosomes from urine by centrifugation at 3,000 g for 10-30 min. Urinary exosomal markers tumor susceptibility gene 101, aquaporin-2, neuron-specific enolase, annexin V, angiotensin-converting enzyme, and podocalyxin (PODXL) were recovered from the nanomembrane concentrator and detected by Western blotting, and typical features of urinary vesicles were found by electron microscopy. Exosomal markers were detected in as little as 0.5 ml of urine. By the nanomembrane method, exosomal proteins could be recovered from urine samples frozen at -80 degrees C or refrigerated overnight at 4 degrees C then stored at -80 degrees C. By enriching exosomes we could detect PODXL, a podocyte marker, which decreased by 71% in five male patients with focal segmental glomerulosclerosis and abundant proteinuria. We conclude that 1) use of a nanomembrane concentrator simplifies and accelerates the enrichment of urinary exosomes; and 2) the nanomembrane concentrator can concentrate exosomal proteins from clinical urine samples. This enhanced method may accelerate the translation of urinary exosomal biomarkers from bench to bedside for the diagnosis, classification, and prognostication of renal diseases.
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PMID:Rapid isolation of urinary exosomal biomarkers using a nanomembrane ultrafiltration concentrator. 1722 75

Mutations in the key enzyme of sialic acid biosynthesis, uridine diphospho-N-acetylglucosamine 2-epimerase/N-acetylmannosamine (ManNAc) kinase (GNE/MNK), result in hereditary inclusion body myopathy (HIBM), an adult-onset, progressive neuromuscular disorder. We created knockin mice harboring the M712T Gne/Mnk mutation. Homozygous mutant (Gne(M712T/M712T)) mice did not survive beyond P3. At P2, significantly decreased Gne-epimerase activity was observed in Gne(M712T/M712T) muscle, but no myopathic features were apparent. Rather, homozygous mutant mice had glomerular hematuria, proteinuria, and podocytopathy. Renal findings included segmental splitting of the glomerular basement membrane, effacement of podocyte foot processes, and reduced sialylation of the major podocyte sialoprotein, podocalyxin. ManNAc administration yielded survival beyond P3 in 43% of the Gne(M712T/M712T) pups. Survivors exhibited improved renal histology, increased sialylation of podocalyxin, and increased Gne/Mnk protein expression and Gne-epimerase activities. These findings establish this Gne(M712T/M712T) knockin mouse as what we believe to be the first genetic model of podocyte injury and segmental glomerular basement membrane splitting due to hyposialylation. The results also support evaluation of ManNAc as a treatment not only for HIBM but also for renal disorders involving proteinuria and hematuria due to podocytopathy and/or segmental splitting of the glomerular basement membrane.
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PMID:Mutation in the key enzyme of sialic acid biosynthesis causes severe glomerular proteinuria and is rescued by N-acetylmannosamine. 1754 51

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