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PubMedDate not supplied

Glomerular podocytes and adhesive interaction with glomerular basement membrane.

Normal podocyte function requires attachment to the underlying glomerular basement membrane. Alteration or disruption of podocyte attachment occurs in many forms of glomerular injury, leading to the development of proteinuria and eventually progressive glomerulosclerosis. The inability of podocytes to proliferate and thereby recover denuded glomerular basement membrane areas may be central to the pathogenesis of certain forms of glomerular diseases.

Animals↗
PubMed2001

Decreased glomerular expression of agrin in diabetic nephropathy and podocytes, cultured in high glucose medium.

AIM: A decrease in glomerular heparan sulfate (HS) proteoglycan (PG), without apparent decrease in HSPG core protein expression, has been reported to occur in diabetic nephropathy (DN). In most studies however, agrin, the major HSPG core protein in the glomerular basement membrane, has not been studied. This prompted us to study the glomerular expression of agrin in parallel to the expression of HS-glycosaminoglycans (GAG) in biopsies of patients with DN. Furthermore, the influence of glucose on agrin production in cultured podocytes and the expression of agrin in fetal kidneys was investigated. METHODS: Cryostat sections of renal biopsies from patients with DN (n = 8) and healthy controls (HC, n = 8), were stained for agrin and HS-GAG. Sections of fetal kidneys were double stained for agrin and CD35 or CD31. Stainings were performed by indirect immunofluorescence (IIF). The production of agrin by cultured human podocytes was tested by ELISA and IIF. RESULTS: The expression of agrin, detected by AS46, was significantly reduced in biopsies from patients with DN compared to HC (p < 0.01). Similar findings were observed when monoclonal antibody JM72 was used (p < 0.05). In addition, a significant reduction in the glomerular expression of HS-GAG was detected with JM403 in these patients (p < 0.01). Agrin is expressed in cultured podocytes, the expression hereof was reduced when the cells were cultured in the presence of 25 mM D-glucose (p < 0.01). In biopsies of human fetal kidneys, glomerular expression of agrin coincided with the expression of CD31. In early stages of glomerular differentiation there was a strong staining for agrin and CD31 while CD35 was only slightly positive. CONCLUSIONS: Our data argue against a selective dysregulation in HSPG sulfation in DN, but suggest a pivotal role for hyperglycemia in the downregulation of agrin core protein production.

Aged↗
PubMed1988

Histochemical characteristics of the basement membranes of the parietal podocytes in the rabbit kidney. A light- and electron-microscopic study.

The patterns of silver affinity and following treatment with guanidine were studied in the basement membrane produced by pareital podocytes induced by corticoids in newborn rabbits. The goal of this study was to analyze the role of the different cell types of the renal corpuscle in the determination of the histochemical characteristics of the glomerular basement membrane (GBM). Jones' method shows that while the GBM exhibited silver affinity only after periodic-acid oxidation, the basement membrane of parietal podocytes exhibits the same histochemical characteristics as the normal parietal basement membrane, appearing deep black both after periodic-acid or permanganate oxidation, and after elastase or lysozyme digestions. Since the treatment with guanidine shows that the basement membrane of the parietal podocytes lacks the endothelial component typical of the GBM, it may be suggested that the special resistance to silver impregnation exhibited by the basement membrane after permanganate oxidation or after different enzymatic digestions is due to its endothelial component.

Animals↗
PubMed2002

The LIM-homeodomain transcription factor Lmx1b plays a crucial role in podocytes.

Patients with nail-patella syndrome often suffer from a nephropathy, which ultimately results in chronic renal failure. The finding that this disease is caused by mutations in the transcription factor LMX1B, which in the kidney is expressed exclusively in podocytes, offers the opportunity for a better understanding of the renal pathogenesis. In our analysis of the nephropathy in nail-patella syndrome, we have made use of the Lmx1b knockout mouse. Transmission electron micrographs showed that glomerular development in general and the differentiation of podocytes in particular were severely impaired. The glomerular capillary network was poorly elaborated, fenestrae in the endothelial cells were largely missing, and the glomerular basement membrane was split. In addition podocytes retained a cuboidal shape and did not form foot processes and slit diaphragms. Expression of the alpha4 chain of collagen IV and of podocin was also severely reduced. Using gel shift assays, we demonstrated that LMX1B bound to two AT-rich sequences in the promoter region of NPHS2, the gene encoding podocin. Our results demonstrate that Lmx1b regulates important steps in glomerular development and establish a link between three hereditary kidney diseases: nail-patella syndrome (Lmx1b), steroid-resistant nephrotic syndrome (podocin), and Alport syndrome (collagen IV alpha4).

Animals↗
PubMed2003

Gamma-secretase activity is dispensable for mesenchyme-to-epithelium transition but required for podocyte and proximal tubule formation in developing mouse kidney.

Notch signaling is involved in pronephros development in Xenopus and in glomerulogenesis in mice. However, owing to early lethality in mice deficient for some Notch pathway genes and functional redundancy for others, a role for Notch signaling during early stages of metanephric development has not been defined. Using an antibody specific to the N-terminal end of gamma-secretase-cleaved Notch1, we found evidence for Notch1 activation in the comma and S-shaped bodies of the mouse metanephros. We therefore cultured mouse metanephroi in the presence of a gamma-secretase inhibitor, N-S-phenyl-glycine-t-butyl ester (DAPT), to block Notch signaling. We observed slightly reduced ureteric bud branching but normal mesenchymal condensation and expression of markers indicating that mesenchyme induction had occurred. However, fewer renal epithelial structures were observed, with a severe deficiency in proximal tubules and glomerular podocytes, which are derived from cells in which activated Notch1 is normally present. Distal tubules were present but in reduced numbers, and this was accompanied by an increase in intervening, non-epithelial cells. After a transient 3-day exposure to DAPT, proximal tubules expanded, but podocyte differentiation failed to recover after removal of DAPT. These observations suggest that gamma-secretase activity, probably through activation of Notch, is required for maintaining a competent progenitor pool as well as for determining the proximal tubule and podocyte fates.

Amyloid Precursor Protein Secretases↗
PubMed2002

Endothelin B receptor-like immunoreactivity in podocytes of the rat kidney.

The distribution of endothelin B receptor (ETBR)-like immunoreactivity in the rat renal glomerulus was investigated using an affinity-purified antibody against a synthetic peptide corresponding to the amino acid residues 425-439 of the rat ETBR. Light microscopy showed ETBR-like immunoreactivity to be localized predominantly near the glomerular blood capillaries. By immunoelectron microscopy using the pre-embedding method, intense immunodeposits indicating ETBR were detected in podocytes, particularly in their foot processes, in contrast with the weak immunoreaction in endothelial cells of the glomerular blood capillaries and in the mesangial cells. In sections stained with the post-embedding method using immunogold particles, positive signals were also found on the plasma membrane of podocyte foot processes as well as the cytoplasm just beneath the cell membrane. These findings suggest that endothelin stimulates ETBR mainly on podocytes, thus resulting in a decrease of the glomerular blood flow and glomerular filtration rates.

Animals↗
PubMed2005

Genetic engineering of glomerular sclerosis in the mouse via control of onset and severity of podocyte-specific injury.

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.

Animals↗
PubMed2001

Acetylcholine increases the free intracellular calcium concentration in podocytes in intact rat glomeruli via muscarinic M(5) receptors.

The effects of acetylcholine (ACh) on the free intracellular calcium concentration ([Ca2+](i)) of microdissected glomeruli were investigated using fura-2 fluorescence digital imaging and two-photon confocal microscopy. ACh caused a concentration-dependent [Ca2+](i) increases with an initial peak followed by a sustained plateau, which was suppressed by reduced extracellular Ca2+ concentrations. The [Ca2+](i) plateau was not affected by the L-type Ca2+ channel blocker nicardipine, whereas gadolinium and lanthanum (both at 1 microM) blocked the plateau. Diphenylacetoxy-N:-methylpiperidine methiodide (100 nM), an M(3)/M(5) receptor antagonist, and pirenzepine (1 microM), an M(1) receptor antagonist, completely inhibited the effect of ACh. [Ca2+](i) measurements using two-photon excitation of fluo-3 and staining of the cells with calcein/acetoxymethyl ester, for observation of the capillary network together with the glomerular cells, showed that [Ca2+](i) was increased in single podocytes. Immunohistochemical studies did not demonstrate M(3) receptor expression in glomerular cells. M(1) receptors could be detected only in the parietal sheet of Bowman's capsule, whereas M(5) receptors were found only in podocytes. The data show that ACh increases [Ca2+](i) in podocytes of intact glomeruli, most likely via muscarinic M(5) receptors.

Acetylcholine↗
PubMed1998

Epitope-specific antibodies to the 43-kD glomerular membrane protein podoplanin cause proteinuria and rapid flattening of podocytes.

The 43-kD integral membrane protein podoplanin is localized on the surface of rat podocytes, and transcriptionally downregulated in rat puromycin nephrosis. In this study, a single intravenous injection of polyclonal rabbit anti-podoplanin IgG resulted in selective binding of IgG to the entire podocyte's surface. Some IgG produced by different rabbits rapidly induced transient proteinuria (approximately 350 mg/24 h at day 1, normal levels around day 5), whereas other IgG were ineffective. All anti-podoplanin IgG shared a common binding site at amino acids 39 to 47 (DDMVNPGLE), whereas IgG inducing glomerular damage specifically bound to an additional epitope at amino acids 74 to 79 (PIEELP), as observed by a SPOTs analysis on overlapping synthetic peptides. Proteinuria was not prevented by complement depletion or by treatment with the oxygen radical scavenger dimethylthiourea. Injection of Fab fragments failed to induce glomerular pathology, indicating that dimerization of podoplanin by divalent IgG was required. Proteinuria was paralleled by extensive flattening of foot processes that was also induced by blood-free perfusion of isolated rat kidneys with anti-podoplanin IgG. Thus, glomerular changes were due to direct interaction of distinct epitope(s) of podoplanin and divalent IgG. These results provide evidence that podoplanin plays a role in maintaining the unique shape of podocyte foot processes and glomerular permeability.

Animals↗
PubMed1985

Glomerular podocytic injury in protein overload proteinuria.

Injection of rats with large doses of bovine serum albumin causes proteinuria which may persist long after the period of overload has ended. In order to assess in this model of proteinuria the relative importance of podocytic epithelial changes versus alterations in anionic groups in the glomerular capillary wall a morphological study has been made of animals in which the kidneys were fixed by vascular perfusion or by in situ drip fixation. By transmission electron microscopy, podocytes showed protein droplets, cytoplasmic vacuoles, spreading of epithelial cytoplasm with loss of foot processes, and focal separation of epithelium from the glomerular basement membrane, occasionally with cytoplasmic disruption. Staining with colloidal iron showed no reduction in the density of anionic groups per unit area on epithelial cell surfaces or elsewhere in glomeruli. However, the reduced surface area of epithelial cells caused by the changes to their structure accounts adequately for the less intense glomerular colloidal iron staining evident by light microscopy. Changes in podocyte structure, particularly those leading to focal cytoplasmic defects on the outer surface of the glomerular basement membrane, appear to be more important than loss of glomerular anionic groups for the development of proteinuria in protein overload nephropathy.

Animals↗
PubMed1975

Intercellular junctions in podocytes of the nephrotic glomerulus as seen with freeze-fracture.

The glomeruli of rats rendered nephrotic by administration of aminonucleoside of puromycin were studied with the freeze-fracture technique. The alterations of the podocytes consisted of a progressive blunting of the foot processes and of the disappearance of the extracellular space normally present between the foot processes at the level of the slit pore. In parallel with the closure of the extracellular space, fracture faces of the plasma membrane of the latered podocytes revealed the presence of peculiar membrane differentiations represented mainly by irregular chains of membrane-associated particles in the fracture face A and by variegated grooves in the fracture face B. The presence of grooves in fracture face B indicates that the chains of particles in fracture face A are likely to be tight junctions rather than linear gap junctions. However, since the presence of continuous ridges is exceptional, it is suggested that the tight junctions are the "leaky" -type and that the podocytes many have only limited capacities for assembling junctions of the "tight" -type.

Animals↗
PubMed1988

Diagnostic and prognostic significance of glomerular epithelial cell vacuolization and podocyte effacement in children with minimal lesion nephrotic syndrome and focal segmental glomerulosclerosis: an ultrastructural study.

Children with minimal lesion nephrotic syndrome (MLNS) may later develop focal segmental glomerulosclerosis (FSGS). It has been suggested that a low percentage of epithelial podocyte effacement (EPE) and a high degree of epithelial cell vacuolization (ECV) in nonsclerotic glomeruli presage FSGS, and that extensive epithelial cell vacuolization in biopsies clearly showing FSGS predicts a poor clinical outcome. To investigate these contentions, we examined by electron microscopy three glomeruli from each of the first biopsies of 30 patients. Ten patients (group 1) had MLNS, 10 (group 2) had FSGS, and 10 (group 3) had MLNS which progressed to FSGS. Clinical data was obtained by retrospective review of medical records. The percent of epithelial podocyte effacement was calculated by computerized linear tracing and epithelial cell vacuolization was scored semiquantitatively from 0-3. (formula; see text) The percent podocyte effacement in each group was the same and does not distinguish MLNS from FSGS. Group 2 had more extensive epithelial cell vacuolization than group 1 (p less than 0.04) and the same as group 3 (p = 0.16). The combined ECV score for groups 2 and 3, however, was significantly greater than for group 1 (p less than 0.025) suggesting that epithelial cell vacuolization may indeed be a marker of FSGS. The extent of epithelial cell vacuolization did not correlate with creatinine clearance at latest follow-up, and thus does not predict clinical outcome.

Adolescent↗
PubMed1988

Ultrastructural organization of contractile and cytoskeletal proteins in glomerular podocytes of chicken, rat, and man.

By immunoelectron microscopy the podocyte foot processes of the rat and human kidney have been shown to contain three major proteins of the contractile apparatus in muscle, i.e., actin, myosin, and the Z-line protein, alpha-actinin. Gel electrophoresis and immunoblot analysis of isolated glomeruli suggests that these proteins constitute an important part of the total glomerular protein contents. In the chicken kidney, the plasmalemmal portion of the foot processes that abuts the glomerular basement membrane was specifically labeled with antibodies against chicken gizzard vinculin and talin, two proteins thought to be important for the linkage of actin filaments to the lipid bilayer and to the receptor for fibronectin and laminin. Such a linkage may not only be important for the attachment of actin filaments to the plasma membrane, but could also be of functional significance for restricting the fibronectin-laminin receptor in its lateral diffusion in the plane of the lipid bilayer and to localize it at the basis of the podocytic foot processes. Assuming that actin, myosin, and alpha-actinin are arranged in a way that would allow the foot processes to generate contractile force this filament system might help the glomerular capillaries to resist the high intraluminal hydrostatic pressure as well as to actively modify the surface area for filtration. Vimentin and tubulin, the main protein subunits of intermediate filaments and microtubules, respectively, were confined to the podocyte cell body and the major processes but were virtually absent from the foot processes. This suggests that both proteins and their polymers are not important for the structure and function of the foot processes.

Actinin↗
PubMed1985

Ultrastructural localization of glycocalyx domains in human kidney podocytes using the lectin-gold technique.

The lectin-gold technique was used to reveal Helix pomatia lectin (HPL)-binding sites in human kidney glomeruli. HPL-binding sites were associated mainly with podocyte foot process bases, and extended over the lamina rara externa of the glomerular basement membrane. In addition, kidneys from blood group A1 donors showed labeling of capillary endothelial cells and erythrocytes. After neuraminidase digestion of the sections prior to incubation with HPL-gold complexes, HPL-binding sites appeared on previously negative regions of the glomerulus. This increase in labeling was particularly striking at the level of the podocyte-free surface (adjacent to the urinary space) in all kidneys, and on capillary endothelial cells from donors of blood groups other than A1. These results demonstrate the existence of two distinct glycocalyx domains in human kidney podocytes, and show the application of the lectin-gold technique for the high resolution, ultrastructural detection and quantification of lectin-binding sites in human material.

Adult↗
PubMedDate not supplied

Induction of MHC class II molecules HLA-DR, -DP and -DQ and ICAM 1 in human podocytes by gamma-interferon.

MHC class II-encoded molecules HLA-DR, -DP and -DQ play a pivotal role in the human immune response. Their constitutive expression is restricted to a number of immunocompetent cells referred to as antigen-presenting cells. However, gamma-interferon (gamma-IFN) has been shown to induce MHC class II molecule expression in several epithelia. Using flow cytometric analysis, we show here that normal and SV40-transformed human podocytes in culture constitutively expressed gamma-IFN receptors. We also show that MHC class I molecules are constitutively expressed in these cells and that HLA-DR, -DP and -DQ expression, which is not found in unstimulated cells, can be induced by gamma-IFN stimulation. This induction was a time-dependent event, a lag phase of 24-48 h being necessary for MHC class II molecules to become detectable at the cell surface by flow cytometric analysis. Induction of MHC class II molecules in human podocytes also showed a concentration dependence, a plateau being reached at a concentration of 500 IU of gamma-IFN/ml of culture medium. This effect was blunted by coincubation of the cells with an antihuman gamma-IFN receptor monoclonal antibody. HLA-DR expression was associated with specific mRNA accumulation, as detected by Northern blot analysis. By indirect immunofluorescence, the intercellular adhesion molecule 1 was also induced by gamma-IFN stimulation. Induction of DR, DP and DQ in human podocytes may be involved in the pathogenesis of immune glomerulonephritis in man.

Blotting, Northern↗
PubMed2005

Focal segmental glomerulosclerosis associated with mitochondrial cytopathy: report of two cases with special emphasis on podocytes.

We report two children with focal segmental glomerulosclerosis (FSGS) associated with mitochondrial cytopathy (MC). Case 1 was diagnosed as MC with the findings of ptosis, ophthalmoplegia, failure to thrive, high serum lactate and pyruvate levels, ragged red fibers in muscle biopsy and the common 4.9 kb deletion in mtDNA when she was four years old. She subsequently developed FSGS four years later. Case 2 was a four month-old girl presenting with feeding difficulty from birth, with vomiting, seizures and nystagmoid eye movements, nephrotic proteinuria and hematuria. Renal biopsy revealed FSGS. Ultrastructural study demonstrated markedly pleomorphic mitochondria in podocytes with a severe effacement of foot processes. The analyses of muscle biopsy and skin fibroblasts for respiratory chain enzymes were found to be normal, while mitochondrial DNA analysis revealed the population of a single deleted mtDNA in the heteroplasmic state. The present cases illustrate FSGS as a rare renal complication of mitochondrial disease and provide further evidence of podocytes possessing abnormal mitochondria which may cause glomerular epithelial cell damage leading to glomerulosclerosis.

Child↗
PubMed2006

Nck links nephrin to actin in kidney podocytes.

Two papers, one in Nature (Jones et al., 2006) and the other in the Journal of Clinical Investigation (Verma et al., 2006) show that Nck adaptor proteins connect phosphorylated nephrin with actin polymerization in podocyte foot processes, structures important for slit-diaphragm formation in the kidney. Their results further our understanding of podocyte development and repair in glomerular disease.

Actins↗
PubMed2006

Clinical impact of research on the podocyte slit diaphragm.

This Review summarizes recent research on the podocyte slit diaphragm. A growing number of molecules that function at the slit diaphragm have been identified in patients with inherited and sporadic nephrotic syndromes. Genetic deletion of nearly all of these molecules results in proteinuria and effacement of foot processes. Nephrin, Neph1 and podocin seem to form a multifunctional receptor complex at the slit diaphragm. Most of the other components of the slit diaphragm interact directly with this complex, in many cases coupling slit diaphragm components to the podocyte's actin cytoskeleton. These molecular findings are being applied to patients with glomerular disease. Over the next decade, these data might help to improve disease classification and prediction of which patients will respond to immunosuppressive treatment.

Gene Expression↗