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)

Recent discoveries in kidney research have given new insights into the molecular make-up of the glomerular filter and mechanisms of permselectivity. The identification of mutations in the genes for glomerular basement membrane type IV collagen has thus demonstrated the central role of the glomerular basement membrane as the structural skeleton of the glomerular capillary. Regional deterioration of this framework not only leads to proteinuria, but also to significant leakage of red blood cells into the urinary space. Tracer studies and the characterization of other glomerular basement membrane components, such as proteoglycans, have also emphasized the role of the glomerular basement membrane in the permselectivity process. However, more recent studies on nephrin, a key component of the slit diaphragm, as well as the podocyte and slit diaphragm-associated intracellular proteins, CD2-associated protein, podocin and alpha-actinin-4, have emphasized the role of the slit diaphragm as a central size-selective filtration barrier. These data have provided a completely new understanding of the mechanisms of proteinuria, both in inherited and acquired diseases. In this review, we present the recent progress made in the characterization of proteins that are important for glomerular permselectivity.
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PMID:Molecular basis of glomerular permselectivity. 1145 36

Mice lacking the 80-kDa CD2-associated protein (CD2AP) develop progressive renal failure that starts soon after birth with proteinuria and foot process effacement by unknown mechanisms. CD2AP has been identified and cloned independently by virtue of its interaction with the T cell protein CD2 and with the docking protein p130Cas. In the present study we examined the localization of CD2AP and p130Cas in the mouse glomerulus and in cultured podocytes. In glomeruli, CD2AP and p130Cas immunofluorescence were observed in podocytes, where they colocalized with F-actin in foot processes. In addition, p130Cas was strongly expressed in mesangial cells. Immunoelectron microscopy demonstrated that CD2AP was present in podocyte foot processes without a prevailing localization. In cultured podocytes, p130Cas was enriched at sites of focal adhesions, where it colocalized like vinculin with F-actin at stress fiber ends. In contrast, CD2AP colocalized with F-actin at the leading edge of lamellipodia and in small spots, which were unevenly distributed in the cytoplasm. The spot-shaped F-actin structures were also stained by antibodies against the actin nucleation Arp2/3 complex and cortactin, both contributing to dynamic actin assembly. Moreover, CD2AP spots in cultured podocytes were in close spatial association with actinin-4, but not actinin-1. Our results suggest that CD2AP and p130Cas, which both colocalize with F-actin in podocytes in situ, possess different functions. Whereas p130Cas is found in focal adhesions, CD2AP seems to be involved in the regulation of highly dynamic F-actin structures in podocyte foot processes.
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PMID:CD2AP and p130Cas localize to different F-actin structures in podocytes. 1155 24

Mutations of NPHS1 or NPHS2, the genes encoding for the glomerular podocyte proteins nephrin and podocin, cause steroid-resistant proteinuria. In addition, mice lacking CD2-associated protein (CD2AP) develop a nephrotic syndrome that resembles NPHS mutations suggesting that all three proteins are essential for the integrity of glomerular podocytes. Although the precise glomerular function of either protein remains unknown, it has been suggested that nephrin forms zipper-like interactions to maintain the structure of podocyte foot processes. We demonstrate now that nephrin is a signaling molecule, which stimulates mitogen-activated protein kinases. Nephrin-induced signaling is greatly enhanced by podocin, which binds to the cytoplasmic tail of nephrin. Mutational analysis suggests that abnormal or inefficient signaling through the nephrin-podocin complex contributes to the development of podocyte dysfunction and proteinuria.
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PMID:Interaction with podocin facilitates nephrin signaling. 1156 57

Recent discoveries in podocyte proteins involved in the renal filtration barrier have shed new light on the ultrastructure of the kidney filter and pathogenesis of proteinuria. The identification of nephrin, a component of the slit diaphragm, and the intracellular slit diaphragm associated proteins CD2AP and podocin has demonstrated the existence of proteins that directly contribute to a functional kidney filter. Mutations in the genes for these three proteins result in proteinuria and nephrotic syndrome, and these proteins are also likely to be involved more generally in the pathomechanisms of proteinuria. This new knowledge has been promoted particularly through the powerful methods of molecular genetics and molecular biology. In this minireview, we present the recent progress in research of the podocyte slit diaphragm.
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PMID:Unraveling the molecular make-up of the glomerular podocyte slit diaphragm. 1170 93

The sieving of plasma components occurs in the kidney through the glomerular capillary wall. This filter is composed of three layers: endothelium, glomerular basement membrane (GBM), and podocyte foot processes connected by slit diaphragms. Defects in this barrier lead to proteinuria and nephrotic syndrome. Previously, defective GBM was regarded to be responsible for proteinuria. However, recent work on genetic diseases has indicated that podocytes and the slit diaphragm are crucial in restricting protein leakage. Congenital nephrotic syndrome of the Finnish type (NPHS1) is caused by mutations in a novel NPHS1 gene, which encodes for a cell adhesion protein, nephrin. This protein is synthesized by podocytes, and seems to be a major component of the slit diaphragm. In severe NPHS1, lack of nephrin leads to missing slit diaphragm. The role of nephrin in acquired kidney diseases remains unknown. In addition to nephrin, other podocyte proteins (podocin, alpha-actinin-4, CD2AP, FAT) have recently been identified and associated with the development of proteinuria. It seems that the slit diaphragm and its interplay with the podocyte cytoskeleton is critical for the normal sieving process, and defects in one of these components easily lead to proteinuria.
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PMID:Genetic kidney diseases disclose the pathogenesis of proteinuria. 1173 Jan 59

These studies examined the expression of the podocyte slit diaphragm protein nephrin and its association with actin at the onset of proteinuria in passive Heymann nephritis (PHN), a rat model of human membranous nephropathy. Four days after immunization, 58% of PHN rats had mild proteinuria. At that time, most slit diaphragms were still visible on electron microscopy; however, in those locations where the deposits encroached on the filtration slits, the slit diaphragms were either displaced or absent. On day 7, the PHN rats were severely proteinuric, and most slit diaphragms were either absent, displaced, or replaced by occluding-type junctions. Immunofluorescence microscopy with antibodies to the external and cytoplasmic domains of nephrin showed a progressive loss of staining and a change in the distribution of nephrin from an interrupted linear pattern in normal controls to a more dispersed and clustered pattern in PHN. In contrast, the intensity of staining for ZO-1 and CD2-associated protein (CD2AP), two other proteins that are located on the cytoplasmic face of the slit diaphragm, was undiminished. Immunogold electron microscopy confirmed the progressive disappearance of nephrin from podocyte foot processes and retention of CD2AP. Glomeruli and glomerular cell membranes were extracted sequentially with Triton X-100, followed by DNase I or potassium iodide to depolymerize actin. Western blot analysis of the extracts showed a progressive decline of total nephrin on days 4 and 7 of PHN as well as a reduction in the actin-associated fraction. These findings show that nephrin partly dissociates from actin at the onset of podocyte injury in PHN. This is accompanied by a progressive loss of nephrin from the podocyte foot processes and prominent changes in the morphology of the slit diaphragms. These events may underlie the loss of podocyte barrier function in membranous nephropathy.
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PMID:Nephrin dissociates from actin, and its expression is reduced in early experimental membranous nephropathy. 1191 54

The study of familial nephrotic syndromes (NS) and the analysis of murine models of glomerular diseases resulted in major progresses in the knowledge of podocyte physiology and pathology. Numerous proteins participating in the composition of the slit diaphragm region have been identified. The importance of several of them (nephrin, podocin, CD2AP, and Neph1) in the maintenance of the glomerular filtration barrier has been demonstrated by the occurrence of massive proteinuria when they are defective. The role of the cytoskeleton has been revealed by the development of proteinuria/NS in patients with ACTN4 mutation and the occurrence of early and severe NS in alpha-actinin-4-deficient mice. Given the genetic heterogeneity of familial NS and the many other genes to be identified, further insights in the molecular basis of the role of the podocyte in the maintenance of the glomerular filtration barrier may be expected in the near future.
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PMID:Podocyte differentiation and hereditary proteinuria/nephrotic syndromes. 1276 Dec 34

Mutations of NPHS1 or NPHS2, the genes encoding nephrin and podocin, as well as the targeted disruption of CD2-associated protein (CD2AP), lead to heavy proteinuria, suggesting that all three proteins are essential for the integrity of glomerular podocytes, the visceral glomerular epithelial cells of the kidney. It has been speculated that these proteins participate in common signaling pathways; however, it has remained unclear which signaling proteins are actually recruited by the slit diaphragm protein complex in vivo. We demonstrate that both nephrin and CD2AP interact with the p85 regulatory subunit of phosphoinositide 3-OH kinase (PI3K) in vivo, recruit PI3K to the plasma membrane, and, together with podocin, stimulate PI3K-dependent AKT signaling in podocytes. Using two-dimensional gel analysis in combination with a phosphoserine-specific antiserum, we demonstrate that the nephrin-induced AKT mediates phosphorylation of several target proteins in podocytes. One such target is Bad; its phosphorylation and inactivation by 14-3-3 protects podocytes against detachment-induced cell death, suggesting that the nephrin-CD2AP-mediated AKT activity can regulate complex biological programs. Our findings reveal a novel role for the slit diaphragm proteins nephrin, CD2AP, and podocin and demonstrate that these three proteins, in addition to their structural functions, initiate PI3K/AKT-dependent signal transduction in glomerular podocytes.
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PMID:Nephrin and CD2AP associate with phosphoinositide 3-OH kinase and stimulate AKT-dependent signaling. 1283 77

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

In the present study, it is shown that mice heterozygous for wt1 develop glomerular sclerosis and the nature and time course of events leading to the glomerular scarring are determined. Wt1-heterozygous (wt1het) mice and their wild-type littermates were closely monitored from birth and plasma levels of urea, creatinine, and albumin were compared with histological data and clinical features. One of the first indications of nephropathy in the wt1het mouse was the development of proteinuria, accompanied by progressive elevation of the plasma levels of urea and creatinine. Subsequently, the mice developed albuminuria, which correlated with thickening of the glomerular basement membrane and fusion of the podocyte foot processes. Glomerulosclerosis was a relatively late event, accompanied by severe albuminuria and loss of WT1, nephrin, CD2AP, and alpha-actinin-4.
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PMID:The wt1-heterozygous mouse; a model to study the development of glomerular sclerosis. 1289 5


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