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PubMed2000

Glomerular expression of dystroglycans is reduced in minimal change nephrosis but not in focal segmental glomerulosclerosis.

Extensive flattening of podocyte foot processes and increased permeability of the glomerular capillary filter are the major pathologic features of minimal change nephrosis (MCN) and focal segmental glomerulosclerosis (FSGS). Adhesion proteins anchor and stabilize podocytes on the glomerular basement membrane (GBM), and presumably are involved in the pathogenesis of foot process flattening. Thus far, ao3 P,-integrin was localized to basal cell membrane domains. In this report, ao- and 3-dystroglycan (DG) were detected at precisely the sa-ne location by immunoelectron microscopy. and the presence of ac- and /-DG chains was confirmed by immunoblotting on isolated human glomeruli. Because the major DG binding partners in the GBM (laminin, agrin, perlecan), and the intracellular dystrophin analogue utrophin are also present in glomeruli, it appears that podocytes adhere to the GBM via DG complexes, similar to muscle fibers in which actin is linked via dystrophin and DG to the extracellular matrix. As with muscle cells, it is therefore plausible that podocytes use precisely actin-guided DG complexes at their "soles" to actively govern the topography of GBM matrix proteins. Expression of the a//3-DG complex was reported to be reduced in muscular dystrophies. and therefore a search for similar pathologic alterations in archival kidney biopsies from patients with MCN (it = 16) and FSGS (ni = 8) was conducted by quantitative immunoelectron microscopy. The density of a-DG on the podocyte's soles was significantly reduced to 25% in MCN, whereas it was not different in normal kidneys and FSGS. The expression of 3-DG was reduced to >50% in MCN, and was slightly increased in FSGS. Levels of DG expression returned to normal in MCN after steroid treatment (7 = 4). Expression of /3-integrin remained at normal levels in all conditions. These findings point to different potentially pathogenic mechanisms of foot process flattening in MCN and FSGS.

Adult↗
PubMed2001

The glomerular epithelial cell anti-adhesin podocalyxin associates with the actin cytoskeleton through interactions with ezrin.

During development, renal glomerular epithelial cells (podocytes) undergo extensive morphologic changes necessary for creation of the glomerular filtration apparatus. These changes include formation of interdigitating foot processes, replacement of tight junctions with slit diaphragms, and the concomitant opening of intercellular urinary spaces. It was postulated previously and confirmed recently that podocalyxin, a sialomucin, plays a major role in maintaining the urinary space open by virtue of the physicochemical properties of its highly negatively charged ectodomain. This study examined whether the highly conserved cytoplasmic tail of podocalyxin also contributes to the unique organization of podocytes by interacting with the cytoskeletal network found in their cell bodies and foot processes. By immunocytochemistry, it was shown that podocalyxin and the actin binding protein ezrin are co-expressed in podocytes and co-localize along the apical plasma membrane, where they form a co-immunoprecipitable complex. Selective detergent extraction followed by differential centrifugation revealed that some of the podocalyxin cosediments with actin filaments. Moreover, its sedimentation is dependent on polymerized actin and is mediated by complex formation with ezrin. Once formed, podocalyxin/ezrin complexes are very stable, because they are insensitive to actin depolymerization or inactivation of Rho kinase, which is known to be necessary for regulation of ezrin and to mediate Rho-dependent actin organization. These data indicate that in podocytes, podocalyxin is complexed with ezrin, which mediates its link to the actin cytoskeleton. Thus, in addition to its ectodomain, the cytoplasmic tail of podocalyxin also likely contributes to maintaining the unique podocyte morphology.

Actins↗
PubMed2002

Nephrin dissociates from actin, and its expression is reduced in early experimental membranous nephropathy.

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.

Actins↗
PubMed2006

Poly(ADP-ribose) polymerase inhibitors ameliorate nephropathy of type 2 diabetic Leprdb/db mice.

The activation of the poly(ADP-ribose) polymerase (PARP) plays an important role in the pathophysiology of various diseases associated with oxidative stress. We found increased amounts of poly(ADP) ribosylated proteins in diabetic kidneys of Lepr(db/db) (BKsJ) mice, suggesting increased PARP activity. Therefore, we examined the effects of two structurally unrelated PARP inhibitors (INO-1001 and PJ-34) on the development of diabetic nephropathy of Lepr(db/db) (BKsJ) mice, an experimental model of type 2 diabetes. INO-1001 and PJ-34 were administered in the drinking water to Lepr(db/db) mice. Both INO-1001 and PJ-34 treatment ameliorated diabetes-induced albumin excretion and mesangial expansion, which are hallmarks of diabetic nephropathy. PARP inhibitors decreased diabetes-induced podocyte depletion in vivo and blocked hyperglycemia-induced podocyte apoptosis in vitro. High glucose treatment of podocytes in vitro led to an early increase of poly(ADP) ribosylated modified protein levels. Reactive oxygen species (ROS) generation appears to be a downstream target of hyperglycemia-induced PARP activation, as PARP inhibitors blocked the hyperglycemia-induced ROS generation in podocytes. INO-1001 and PJ-34 also normalized the hyperglycemia-induced mitochondrial depolarization. PARP blockade by INO-1001 and PJ-34 prevented hyperglycemia-induced nuclear factor-kappaB (NFkappaB) activation of podocytes, and it was made evident by the inhibitor of kappaBalpha phosphorylation and NFkappaB p50 nuclear translocation. Our results indicate that hyperglycemia-induced PARP activation plays an important role in the pathogenesis of glomerulopathy associated with type 2 diabetes and could serve as a novel therapeutic target.

Animals↗
PubMed2001

Genetic kidney diseases disclose the pathogenesis of proteinuria.

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.

Glomerulosclerosis, Focal Segmental↗
PubMed2002

[New findings on the pathogenesis of nephrotic syndrome (review article)].

Increased glomerular permeability of the glomerular capillary wall for macromolecules caused by the changes of the structure of the glomerular basement membrane, or podocytes and slit diaphragm between foot processes of podocytes is the main cause of nephrotic syndrome. Recently new information about podocyte proteins emerged. Mutation of the basic structural protein of slit diaphragm, nephrin, results in the Finnish type of the congenital nephrotic syndrome, mutations of other podocyte proteins, e.g. podocin, or alpha-actinin-4 result in congenital focal segmental glomerulosclerosis. Primary focal segmental glomerulosclerosis is a clinical syndrome, caused either by the mutation of podocyte proteins, or by circulating permeability factors, or by the deficiency of their circulating inhibitors. New information about the role of cubilin and megalin in the reabsorption of filtered albumin in the proximal tubule may contribute to the elucidation of the mechanisms of the tubulotoxicity of proteinuria; inhibition of albumin reabsorption in nephrotic subjects could lower the risk of interstitial fibrosis and progressive renal insufficiency.

Humans↗
PubMed1988

Presence of the C3b complement receptor (CR1) antigen in the glomerular basement membrane of human fetal kidneys.

The distribution pattern of the C3b receptor (CR1) antigen, one of the earliest differentiation markers of the podocyte plasma membrane, has been studied during human renal ontogenesis by indirect immunofluorescence and immunoelectronmicroscopy using Fab'2 fragments of anti-CR1 antibodies. CR1 antigen has been detected at the open-stage glomerulus, which precedes constriction of the vascular pole, along the capillary wall, in a thick and homogeneous pattern of staining. By immunoelectronmicroscopy, CR1 antigen was present on the porocyte plasma membrane towards the glomerular basement membrane (GBM), and diffusely distributed within the GBM according to a decreasing intensity gradient from podocytes to endothelial cells. At a later stage of differentiation ('closed' glomerulus stage) when constriction of the vascular pole has occurred, the podocyte plasma membrane appeared diffusely labelled for CR1; the GBM was also stained with a decreasing intensity gradient from podocytes to endothelial cells. This result indicates that a plasma membrane receptor belonging to the cell coat of podocytes can be found in the extracellular space within the GBM. Thus the antigenic repertoire of the GBM of human fetal kidney comprises antigens of constituent molecules of the extracellular matrix and planted antigens originating from adjacent cells.

Basement Membrane↗
PubMed1988

Occurrence and distribution of sialic acid residues in developing rat glomerulus: investigations with the Limax flavus and the wheat germ agglutinin.

Evidence has accumulated suggesting that cell surface sialic acid is required for the development and maintenance of the specialized shape of glomerular podocytes in kidney. We have investigated the occurrence and distribution of plasma membrane sialic acid residues during glomerulus development in newborn rat kidney with special attention to the differentiating podocytes. Terminal sialic acid residues were detected with a high resolution cytochemical lectin technique applying the Limax flavus agglutinin in conjunction with the fetuin-gold complex. In addition, the wheat germ agglutinin/ovomucoid-gold technique was performed. Lectin binding, indicative of the presence of terminal sialic acid residues in glycoconjugates, was found in the plasma membrane of the cells of the nephrogenic cap, the earliest stage of glomerulus development. Label of similar intensity was found in the apical, lateral and basal plasma membrane of all cell types in later developmental stages such as renal vesicle, S-shaped body, capillary loop stage and maturing glomeruli. Considering the podocytes, already the presumptive podocytes clearly identifiable in the S-shaped body and early capillary loop stage exhibited binding sites for the Limax flavus and the wheat germ agglutinin along their plasma membrane domains irrespective of the position of the tight junctions and before foot process and slit diaphragm formation occurred. These results demonstrate that in the plasma membrane of all cell types during the different stages of glomerulus development sialylated glycoconjugates are present. They indicate that the general occurrence of sialic acid residues does not coincide with the development of foot processes and slit diaphragms of glomerular podocytes.

Animals↗
PubMed1985

Enzymatic dissection of the glomerulus.

White rat kidneys were fixed in perfusion, postfixed with 10% glutaraldehyde, and cut into 1-mm slices. The slices were treated with a sequential digestion over 4 days with trypsin, pepsin, and pronase E. This treatment dissolved the glomerular basement membrane and the mesangial matrix. Teasing the slides in buffer released many glomeruli and tubules which were prepared for scanning electron microscopy while attached to gelatine glass cover slips. Four human renal biopsies were similarly treated. The enzymatic removal of the basement membrane permitted viewing of the basilar or capillary slide of loosened podocytes and their processes. The cell body of the podocytes often exhibited a considerable area of contact with the basement membrane. The primary and secondary podocyte processes and foot processes maintained a continuous contact with the basement membrane. Human podocytes, although larger, were similar to the rat. Podocytes from minimal change disease showed severe retraction and flattening of primary and secondary processes and foot processes. Extensive visualization of the basilar surface of the exposed endothelial tubes was possible with this technique. The fenestrated and nonfenestrated portions were revealed including the axial area where the endothelial cells contact the mesangial cells and matrix, which formed an impression on the surface of the endothelium. The mesangial cells and their connecting processes (the mesangial network) were revealed extending from the peripheral lobule to the glomerular hilus where they merged with lacis cells. The mesangial cells exhibited a variety of processes which anchored into the mesangial matrix. At the hilus, these cells assumed a flat, villous, lacy appearance, and these cells encircled the large hilar capillaries. Glomeruli with afferent and efferent arterioles and associated Goormaghtigh (lacis) cells were identified. The transition between mesangial, Goormaghtigh, and smooth muscle cells was observed. These observations provide a unique view of the organization of the rat and human glomerulus and suggest the potential for the use of the present technique in the study of diseased glomeruli.

Animals↗
PubMed1983

Cytoplasmic contractile elements in glomerular cells.

The presence and possible roles of cytoplasmic contractile elements in glomerular epithelial podocytes and the glomerular mesangium are briefly discussed. Glomerular podocytes contain actinlike filaments distributed throughout their cytoplasm and more concentrated filamentous material within their foot processes. Antibody labeling and nitrobenzoxadiazole-phallacidin labeling have confirmed the presence of especially high concentrations of actin within podocyte foot processes. Studies with cytochalasins have suggested that contraction of actin within podocytes leads to a flattening of foot processes and a loss of the intervening filtration slits. Conversely, relaxation of these contractile elements leads to a narrowing of the bases of foot processes and an increase in the number of fully open intervening filtration slits. These observations have led to the proposal that glomerular podocytes have the potential to regulate the glomerular filtration rate by changing the shapes of their foot processes and thereby decreasing or increasing the number of filtration slits available for solute efflux across the glomerular wall. There is also evidence to indicate the presence of contractile elements within the glomerular mesangium. These contractile elements may be represented in part by bundles of fine filaments associated with electron-dense bodies that are present within many processes that radiate from these cells. In vitro studies in particular have suggested that these cells may possess contractile properties. It has been proposed that contraction of the mesangial cells may lead to a shunting of blood within the glomerulus or to a decrease in glomerular size.

Actins↗
PubMed1995

[A study of urinary podocalyxin in children with IgA nephropathy].

The existence of podocalyxin (PCX) in urine sediments of 30 children with IgA nephropathy was identified by positive findings of immunofluorescence testing using a monoclonal antibody (PHM-5). Three structures (cells (podocytes), casts, granules) were stained and arbitrarily scored according to their numbers and intensity of fluorescence. The urinary scores for podocytes and casts were higher in the acute stage than in the chronic stage (p < 0.02 and p < 0.01, respectively). Protein excretion and hematuria showed a strong parallel correlation in the podocytes (p < 0.005 and p < 0.001), and in the casts (p < 0.001 and p < 0.005) in the urine sediments. The urinary scores for podocytes and casts were significantly higher in cases with extracapillary lesions (p < 0.003 and p < 0.01) and with interstitial lesions (p < 0.02 and p < 0.008) but no correlation existed with the intensity of mesangial proliferation. The urinary scores for podocytes and casts were also higher in cases with mesangiocapillary IgA deposits (p < 0.04 and p < 0.04) and C 3 deposits (p < 0.03 and p < 0.04). These findings suggest that PCX in the urine sediments indicate the degree of the glomerular epithelial cell injury and is useful for clinical evaluations.

Adolescent↗
PubMed1996

Glomerular epithelial protein 1 and podocalyxin-like protein 1 in inflammatory glomerular disease (crescentic nephritis) in rabbit and man.

The podocyte is the cell responsible in large part for maintaining the glomerular filtration barrier. Glomerular epithelial protein 1 (GLEPP1) is a novel receptor-like transmembrane protein tyrosine phosphatase present on the apical surface of podocyte foot processes. Podocalyxin-like protein 1 (PCLP1) is a transmembrane sialoglycoprotein which is also present on the foot process apical surface as well as on the surface of endothelial cells. GLEPP1 and PCLP1 are thought to play a role in regulating the structure and function of podocyte foot processes. Glomerular injury affecting the podocyte is likely to be reflected by changes in these proteins. GLEPP1 distribution in human renal biopsy with inflammatory glomerular disease and crescent formation was examined by immunocytochemistry. A model of inflammatory glomerular injury induced by guinea pig anti-rabbit basement membrane (anti-GBM) antibody was used to examine the distribution and amount of GLEPP1 and PCLP1 mRNA and protein. A biopsy study was done to determine whether the extent of GLEPP1 depletion from glomeruli at early time points (Day 7) would predict the severity of crescent formation at Day 30. Glomeruli from human renal biopsies with crescentic nephritis showed focal to diffuse disappearance of GLEPP1 protein. No GLEPP1 was present within the cellular crescent. By Day 4 of the rabbit anti-GBM model, before cellular crescents had formed, GLEPP1 protein was reduced from 127 +/- 28 X 10(7) to 30 +/- 5 X 10(7) molecules per glomerulus (p < 0.001), and GLEPP1 mRNA was reduced by 62% (p < 0.05). In contrast, at this time there was no significant reduction of PCLP1 protein from the normal number of 309 X 10(9) molecules per glomerulus and the PCLP1 mRNA level had not decreased. At Day 4, podocyte foot processes were effaced and proteinuria was present. Glomerular culture supernatants from Day 4 rabbits caused a reduction in GLEPP1 but not PCLP1 protein expression by cultured normal glomeruli, showing that a soluble factor was produced at Day 4 which reduced the number of GLEPP1 molecules in glomeruli. There was no detectable proteolysis of GLEPP1 or PCLP1 in glomeruli and no increase in GLEPP1 or PCLP1 excretion in urine. Therefore, the reduction in glomerular GLEPP1 was associated with reduced synthetic capacity. The proportion of glomeruli with reduced GLEPP1 at Day 7 of the model was significantly associated with the percent of glomeruli which had formed crescents at Day 30 (r = 0.86, p < 0.0001). GLEPP1 appears to be a sensitive indicator of glomerular injury during inflammation in man and in the rabbit model. A reduction in amount of GLEPP1 is associated with worse outcome for the glomerulus.

Animals↗
PubMedDate not supplied

Characterization of a rat glomerular visceral epithelial cell line.

Cultures of glomerular epithelial cells (GEC) are currently used to identify important cellular and molecular mechanisms involved in the pathogenesis of renal diseases. However, there is still controversy in the literature as to the visceral or parietal origin of cultured GEC. Our aim was to firmly establish the nature of a GEC cell line. The reactivity of cultured GEC was investigated with a large panel of mono- and polyclonal antibodies by using immunofluorescent techniques and compared with literature data on the in vivo expression of these antigens on podocytes. In addition, the podocyte specific 5A (podocalyxin), 13A and 27A (9-O-acetylated GD3) antigen expression was investigated in immuno-overlay experiments with isolated gangliosides and in immunoprecipitations with metabolically labelled cells. In general, immunoreactivities between cultured GEC and literature data on GEC in vivo expressions were similar. Important podocyte epitopes in vivo were expressed by cultured GEC such as podocalyxin, gp330 and the 13A antigen. Cultured GEC however differed from their in vivo counterparts in their expression of keratin-18, their lack of expression of pp44 and no detectable immunohistological expression of the ganglioside 9-O-acetylated GD3. Interestingly, the podocyte-specific epitope 9-O-acetylated GD3 was detected by the 27A antibodies in immuno-overlays of isolated GEC gangliosides. Moreover, by using the 27A antibody, we were able to precipitate the podocyte-specific 103-kD protein from 35S-methionine metabolically labelled GEC. From our immunohistological data together with the detectability of the 27A antigen we conclude that the cell line we use very probably originates from glomerular visceral epithelial cells.

Animals↗
PubMed1998

novH: differential expression in developing kidney and Wilm's tumors.

We previously established that the expression of the human nov gene (novH) was altered in Wilms' tumors and that levels of novH and WT1 mRNA were inversely correlated in individual Wilms' tumors. Insofar as novH has been shown to be a target for WT1 regulation, novH might play an important role during normal nephrogenesis and in the development of Wilms' tumors. We now show that during normal nephrogenesis novH protein is tightly associated with differentiation of glomerular podocytes. NovH expression is not restricted to renal differentiation but is also detected in endothelium and neural tissue of the kidney. Our results establish that alteration of novH expression in sporadic and heritable Wilms' tumors is associated with dysregulated expression of both novH mRNA and protein. In general, the highest novH expression was noted in the Wilms' tumor, genitourinary anomalies, aniridia, and mental retardation (WAGR)-associated Wilms' tumors. Expression in the Denys-Drash syndrome (DDS)-associated Wilms' tumors fell within the variable spectrum observed in sporadic Wilms' tumor cases. As in developing kidney podocytes, novH protein was also prominent in the abnormal hypoplastic podocytes from DDS cases and in kidney podocytes adjoining Wilms' tumors. In Wilms' tumors exhibiting heterotypic differentiation, novH protein was expressed at high levels in tumor-derived striated muscle and at lower levels in tumor-derived cartilage. These observations taken together indicate that novH may represent both a marker of podocytic differentiation in kidney and a marker of heterotypic mesenchymal differentiation in Wilms' tumors. In addition, absence or very low levels of WT1 are correlated with higher novH expression, and its variable expression in cases with mutant WT1 (sporadic and DDS) suggests that the potential activation and repression transcriptional functions possessed by WT1 are likely dependent on the specific mutation incurred.

Animals↗
PubMed2006

Rat nephrin modulates cell morphology via the adaptor protein Nck.

Nephrin is a transmembrane molecule essential for morphology and function of kidney podocytes. We and others reported previously that the cytoplasmic domain of human and mouse nephrin interacts with the adaptor protein, Nck, in a tyrosine phosphorylation-dependent manner. In the current study, we characterized the interaction of rat nephrin with Nck and further addressed its impact on cell morphology. Rat nephrin expressed in Cos-1 cells co-immunoprecipitated with Nck in a manner dependent on the phosphorylation of Y1204 and Y1228. Nephrin from normal rat glomeruli was also tyrosine phosphorylated and associated with Nck. Overexpression of rat nephrin in HEK293T cells induced morphological changes resembling process formation, which became more distinct when the extracellular domain of nephrin was cross-linked by antibodies. The morphological changes were attenuated by expression of dominant negative constructs of Nck. In the rat model of podocyte injury and proteinuria, nephrin tyrosine phosphorylation and nephrin-Nck interaction were both reduced significantly. Taken together, we propose that Nck couples nephrin to the actin cytoskeleton in glomerular podocytes and contributes to the maintenance of normal morphology and function of podocytes.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Expression of synaptopodin and GLEPP1 as markers of steroid responsiveness in primary focal segmental glomerulosclerosis.

The crucial involvement of podocyte failure in the development of hereditary focal segmental glomerulosclerosis (FSGS) indicates that specific podocyte proteins are closely related to podocyte function and biology. We hypothesized that podocyte failure, reflected by alteration of these proteins, leads not only to FSGS but also to resistance to steroid therapy. We investigated the association between expression of synaptopodin and glomerular epithelial protein 1 (GLEPP1) and response to corticosteroid therapy in primary FSGS. The subjects of this retrospective study were 17 adult patients with primary FSGS with nephrotic syndrome (NS) seen at Fukuoka Red Cross Hospital between 1979 and 2001. They were divided into two groups according to the response to steroid therapy at 6months: responders (n=10) and non-responders (persistence of nephrotic-range proteinuria, n=7). Expression levels of synaptopodin and GLEPP1 were examined immunohistochemically using image analysis software. Low expression levels of both proteins were associated with poor steroid responsiveness in FSGS. The average gray values for synaptopodin and GLEPP1 expression in responders vs. non-responders were 9.0+/-0.7 (mean+/-S.E.M.) vs. 6.3+/-0.9 (P=0.04) and 9.6+/-1.2 vs. 6.0+/-1.0 (P=0.04), respectively. The percentages of glomerular area staining for synaptopodin and GLEPP1 in responders vs. non-responders were 15.4+/-2.7% vs. 8.1+/-1.2% (P=0.045) and 11.9+/-1.6% vs. 6.0+/-1.3% (P=0.02), respectively. Synaptopodin expression correlated with the severity of proteinuria and with GLEPP1 expression. Reduced expression of both synaptopodin and GLEPP1 is associated with poor response to steroid therapy in primary FSGS.

Adult↗
PubMed2005

MAGI-1 is a component of the glomerular slit diaphragm that is tightly associated with nephrin.

MAGUK with inverted domain structure-1 (MAGI-1) is a membrane-associated protein with one guanylate kinase, six PSD-95/Dlg-A/ZO-1 (PDZ), and two WW domains and is localized at tight junctions in epithelial cells. MAGI-1 interacts with various proteins and is proposed to function as a scaffold protein. In the previous study, we discovered a MAGI-1-interacting cell adhesion molecule junctional adhesion molecule 4 (JAM4). Both proteins are highly expressed in glomerular podocytes in the kidney and partially colocalized. In this study, we have further searched for a binding partner of MAGI-1 in the kidney through yeast two-hybrid screening and obtained nephrin. Nephrin is a cell adhesion molecule specifically localized at the slit diaphragm between neighboring foot processes of podocytes. Biochemical studies reveal that nephrin directly binds to the middle PDZ domains of MAGI-1 through its carboxyl terminus but does not bind to ZO-1. MAGI-1 forms a tripartite complex with nephrin and JAM4 in vitro. Immunoelectron microscopy shows that the localization of MAGI-1 is restricted to the slit diaphragm, whereas JAM4 is also distributed on apical membranes of podocytes. In puromycin aminonucleoside-induced nephrotic podocytes, MAGI-1 is localized with nephrin at the displaced slit diaphragm. These data indicate that MAGI-1 is a component of the slit diaphragm and tightly interacts with nephrin and JAM4 in vivo. MAGI-1 may play a role in determining the boundary between the apical and the bosolateral domain at the level of slit diaphragm.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Fabry disease: a morphologic study of 11 cases.

Fabry disease is a metabolic disorder caused by the genetic deficiency of alpha-galactosidase A. Deposition of glycosphingolipids in podocytes, endothelial cells, and other cell types leads to formation of myelin-like inclusions, which are the hallmark of the disease. In most untreated males, the disorder progresses to end-stage kidney disease. Fabry disease is rare, and no renal biopsy series focusing on pathologic findings has been published in the past 25 years. We retrieved kidney biopsies diagnosed with Fabry disease from our files, and reviewed clinical data as well as the light and electron microscopy. In total, 11 patients were identified: six male subjects aged 17-43 years and five female subjects aged 30-73 years. On average, male patients presented more than 10 years earlier then female patients. A total of 10 patients had proteinuria, two with the nephrotic syndrome. Four male and three female patients had decreased renal function. Light microscopy showed vacuolization of the podocyte cytoplasm and variable glomerular sclerosis. Older patients and males had more advanced glomerular and interstitial sclerosis, but three of the five female patients also had advanced renal disease. Electron microscopy showed the characteristic myelin-like inclusions most prominently in the podocyte cytoplasm. Seven patients also had podocyte foot process effacement. A second type of deposit, unexpected and conspicuous, was identified in three males, and found to be associated with glomerular basement membrane duplications. These deposits were composed of layered membrane-like material, and therefore morphologically distinct from myelin-like inclusions. They probably represent remnants of damaged endothelial cells.

Adolescent↗