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PubMed1996

A frequent pathway to glomerulosclerosis: deterioration of tuft architecture-podocyte damage-segmental sclerosis.

Lesions in glomerular architecture include mesangial expansion, capillary ballooning, capillary unfolding and microaneurysm formation. Such lesions appear to develop in response to mechanical overextension. A frequent pathway to segmental glomerulosclerosis starts from capillary ballooning and unfolding. Podocytes supporting those deranged capillaries are exposed to increased mechanical stress. This may lead to podocyte injury terminating in detachments from the GBM. Naked GBM areas at peripheral capillary loops allow the attachment of parietal cells to the GBM, i.e. the formation of a tuft adhesion to Bowman's capsule. An adhesion has a strong tendency to progress to segmental sclerosis.

Animals↗
PubMed1997

Angiotensin II depolarizes podocytes in the intact glomerulus of the Rat.

The aim of this study was to examine the effects of angiotensin II (Ang II) on cellular functions of rat podocytes (pod) in the intact freshly isolated glomerulus and in culture. Membrane voltage (Vm) and ion currents of pod were examined with the patch clamp technique in fast whole cell and whole cell nystatin configuration. Vm of pod was -38+/-1 mV (n = 86). Ang II led to a concentration-dependent depolarization of pod with an ED50 of 10(-8) mol/liter. In the presence of Ang II (10(-7) mol/liter, n = 20), pod depolarized by 7+/-1 mV. In an extracellular solution with a reduced Cl- concentration of 32 mmol/liter, the effect of Ang II on Vm was significantly increased to 14+/-4 mV (n = 8). The depolarization induced by Ang II was neither inhibited in an extracellular Na+-free solution nor in a solution with a reduced extracellular Ca2+ (down to 1 micromol/liter). Like Ang II, the calcium ionophore A23187 (10(-5) mol/liter, n = 9) depolarized pod by 10+/-2 mV, whereas forskolin (10(-5) mol/liter), 8-(4-chlorophenylthio)-cAMP and N2,2'-o-dibutyryl-cGMP (both 5 x 10(-4) mol/liter) did not alter Vm of pod. The angiotensin 1 receptor antagonist losartan (10(-7) mol/liter) completely inhibited the Ang II-induced (10(-7) mol/liter) depolarization (n = 5). Like pod in the glomerulus, pod in short term culture depolarized in response to Ang II (10(-8) mol/liter, n = 5). Our results suggest that Ang II depolarizes podocytes directly by opening a Cl- conductance. The activation of this ion conductance is mediated by an AT1 receptor and may be regulated by the intracellular Ca2+ activity.

Angiotensin II↗
PubMed2003

NAD(P)H: quinone oxidoreductase 1 expression in kidney podocytes.

NAD(P)H:quinone oxidoreductase 1 (NQO1; DT-diaphorase; DTD) is a cytosolic two-electron reductase, and compounds of the quinone family such as mitomycin C are efficiently bioactivated by this enzyme. The observation that DT-diaphorase is highly expressed in many cancerous tissues compared to normal tissues has provided us with a potentially selective target that can be exploited in the design of novel anticancer agents. Because of the relative lack of information about the cell-specific expression of DT-diaphorase, the purpose of this study was to map the distribution of this enzyme in normal human tissues. Fifteen tissue samples from normal human kidney were analyzed for expression of DT-diaphorase by immunohistochemistry (two-step indirect method). We found a specific high expression of DT-diaphorase in glomerular visceral epithelial cells (podocytes). These results suggest that a high expression of DT-diaphorase in podocytes could play a major role in the pathogenesis of renal toxicity and mitomycin C-induced hemolytic uremic syndrome, in which injury to the glomerular filtration mechanism is the primary damage, leading to a cascade of deleterious events including microangiopathic hemolytic anemia and thrombocytopenia. This observation has potential therapeutic implications because the DT-diaphorase metabolic pathway is influenced by many agents, including drugs, diet, and environmental cell factors such as pH and oxygen tension.

Humans↗
PubMed1979

Podocytes in aminonucleoside glomerulonephritis investigated ultrastructurally with concanavalin A.

Peroxidase labeled concanavalin A (Con A) permits the detection of some saccharide determinants. This histochemical technique permits the visualization of cellular pathological modifications not observed with other methods. Its use in an ultrastructural study of nephritis induced by a single injection of aminonucleoside demonstrated the following in podocytes. The Con A positive endoplasmic reticulum (ER), essentially the rough ER, lost its normal linear and network appearance to take on a dot dash pattern. ER contents but not attached ribosomes and membranes were Con A positive. The dot dash pattern, due to a fragmentation of the ER, appeared prior to the onset of proteinuria and was attenuated before the disappearance of proteinuria. These changes of the ER were not observed in other proteinuric states. This suggests that aminonucleoside can damage the synthesis apparatus of podocytes, revealed by the Con A method.

Animals↗
PubMed1995

Fine structure of podocytes in the bovine renal corpuscle.

Thick primary processes issued from the hemispherical or plate-like cell bodies of podocytes in bovine renal corpuscles. These processes branched into secondary and tertiary ones, but no fine pedicels were observed on the outer surface of the podocytes by scanning electron microscopy, because each primary process closely interdigitated with those of adjacent cells. Many pedicels, however, were observed under the processes by using the freeze-fractograph and a transmission electron microscope.

Aging↗
PubMed2005

NEPH2 is located at the glomerular slit diaphragm, interacts with nephrin and is cleaved from podocytes by metalloproteinases.

The NEPH family comprises three transmembrane proteins of the Ig superfamily interacting with the glomerular slit diaphragm proteins podocin and ZO-1. NEPH1 binds to nephrin, another component of the slit diaphragm, and loss of either partner causes heavy proteinuria. NEPH2, which is strongly conserved among a large number of species, is also expressed in the kidney; however, its function is unknown. The authors raised NEPH2 antisera to demonstrate NEPH2 expression in a variety of mouse tissues, including the kidney and a podocyte cell line. The authors localized the expression of NEPH2 to the glomerular slit diaphragm by electron microscopy and show NEPH2 homodimerization and specific interactions with the extracellular domain of nephrin in vitro and in vivo. NEPH1, however, failed to interact with NEPH2. The authors detected immunoreactive NEPH2 in urine of healthy subjects, suggesting that the extracellular domain is cleaved under physiologic conditions. These findings were confirmed in vitro in podocyte cell culture. Shedding is increased by tyrosine phosphatase inhibitors and diminished by GM6001, an inhibitor of metalloproteinases. Overexpression experiments indicate an involvement of the MT1-matrix metalloproteinase. The results suggest a role for NEPH2 in the organization and/or maintenance of the glomerular slit diaphragm that may differ from the functions of NEPH1 and nephrin.

Animals↗
PubMed2001

The membrane-associated guanylate kinase protein MAGI-1 binds megalin and is present in glomerular podocytes.

The transmembrane endocytic receptor glycoprotein 330/megalin (hereafter referred to as megalin) is localized to the apical membrane domain of epithelial cells, where it is involved in the uptake of proteins from extracellular sources. The cytoplasmic domain of megalin contains amino acid motifs that have the potential to bind to other proteins, which may influence its localization or function. The yeast two-hybrid system was used to search for proteins that bind to the cytoplasmic tail of megalin, and a protein fragment from a mouse embryonic cDNA library that contained a single PDZ domain was identified. This protein, which was named glycoprotein 330-associated protein (GASP), appears to be a truncated mouse counterpart of the human and rat proteins atrophin-1-interacting protein-1 and synaptic scaffolding molecule, respectively. The interaction of GASP with megalin is mediated by the PDZ domain of GASP binding to the DSDV motif found at the carboxyl-terminus of megalin. A mutant version of megalin that lacks the terminal valine is unable to bind to GASP, illustrating the PDZ domain-dependent interaction between these two proteins. A close homolog of GASP, i.e., membrane-associated guanylate kinase with inverted orientation-1 (MAGI-1), is more ubiquitous in its tissue distribution (including kidney) and is also able to specifically bind to megalin via its fifth PDZ domain. Immunofluorescence studies of adult kidney revealed that MAGI-1 is expressed in the glomerulus of the kidney, in a manner that parallels the expression of the podocyte-specific protein glomerular epithelial protein 1. Western analysis of endogenous MAGI-1 from glomerular preparations suggests that it is associated with the cytoskeleton and seems to be expressed in a different form, compared with cell line-derived endogenous MAGI-1. The association of megalin with MAGI-1 may allow the assembly of a multiprotein complex, in which megalin may serve a nonendocytic function in glomerular podocytes.

Amino Acid Sequence↗
PubMed1999

[Regulation of the microtubule-dependent process formation. A review based on a comparison between the neuron and the renal glomerular podocyte].

Microtubular cytoskeletons play a crucial role in the morphogenesis of process-bearing cells, such as the neuron and the renal glomerular podocyte. Microtubules are bundled and stabilized by various microtubule-associated proteins, providing a mechanical basis to maintain the deviated morphology of cell processes. To support the process morphology, microtubules are also associated with other cytoskeletal elements such as actin and intermediate filaments. The microtubular polarity is uniformly plus-end-distal in neuronal axons, whereas in dendrites as well as in podocytes, the polarity is revealed to be non-uniform (i.e., both plus-end-distal and minus-end-distal microtubules are present in cell processes). Recently, this non-uniformity is reported to be established by a microtubule-dependent motor protein. Motor proteins are capable to drive the intracellular transport of cytoskeletal elements in addition to that of membrane vesicles. It is still an open question whether cytoskeletal elements are transported along cell processes as subunits or as polymers.

Animals↗
PubMed1992

Cytoskeleton of podocytes in vertebrate animals and human.

Using TEM and immunofluorescence microscope, a study was made on podocytes in vertebrates where an intermediate-sized filament system is replaced by a microtubule system, accompanied by highly developed microfilaments structures. A comparative immunofluorescence study was carried out on cryotome renal sections of plaice (Pleuronectes platessa L.) and rats, using specific antibodies anti-cytokeratins and anti-vimentin. With polyclonal anti-vimentin serum the capillaries of the renal glomeruli showed a bright colour of plaice and only a week one in the rats. Double staining of renal tissue of mongrel rats of different ages (6-7 weeks and 1.8 years old) with antibodies for actin and anti-vimentin polyclonal serum revealed in young rats an intensive fluorescence for actin and a slight fluorescence for the intermediate filaments. Renal glomeruli of old rats demonstrate a strong vimentin-activity and lower actin one. The ultrastructural study of human podocytes showed two different cytoskeleton age-depending types (2, 4, 6, 37 and 65 years old). It is suggested that during individual development and ageing in kidneys of higher animals and human, physiological changes induce morphological cytoskeleton restructuration accompanied by intensive development of intermediate filaments and simultaneous "involution" of microtubules and microfilaments.

Actins↗
PubMed2005

[Podocytopathie and transdifferentiation of the podocytes in human glomerulonephritis. An immunomorphological study].

Transdifferentiation is characterized by a loss of normal epitopes by differentiated cells, accompanied by the acquisition of new epitopes and new functions. Podocytes are differentiated epithelial cells that cover and adhere to the outer surface of the glomerular basement membrane (GBM). The podocyte/GBM complex contributes to the selective filter function of the glomerular tuft. We have shown that, in various human glomerulonephritides, "dysregulated" podocytes acquire the potential to proliferate and multiply, undergo profound morphologic changes, detach from the GBM, and show phenotypic changes indicative of transdifferentiation. In the course of these events they lose their original epitopes and acquire macrophagic markers.

Basement Membrane↗
PubMed1991

Timed acid bath effects on kidney podocytes prepared for scanning electron microscopy.

In perfusion fixation of dog kidney glomeruli, observation of tear fractured surfaces by scanning electron microscopy reveals the deposition of "debris" on the surface of glomerular visceral epithelium (podocytes) that is not deposited on other kidney tissue surfaces. It is of concern to remove this debris without damage to tissue surfaces. A 5 minute bath in 8N HCl (hydrochloric acid) following postfixation in 1% OsO4 (osmium tetroxide) removes only some of the debris. A 10 minute acid bath removes this debris without visible damage to podocyte surface structures such as cilia, plicae or blebs. A 20 minute acid bath is destructive to these surface features.

Animals↗
PubMed1990

[The dynamics of the changes in the ultrastructural organization of the podocytes in the primary nephrotic syndrome in children].

Combined clinico-morphological (including electronmicroscopy) study of kidney biopsies from 68 children has been performed. A group of 15 children, aged from 3 to 12 years suffering from nephrotic syndrome with minimal glomerular changes was separated. The biopsies were taken at the beginning of the disease, in the period of the most pronounced symptoms of nephrotic syndrome and during the clinical remission after the disappearance of proteinuria at the end of hormonotherapy (prednisolone). The reactive changes of the podocyte ultrastructural organization under functional stress are described as well as disturbance of membranous and non-membranous organellas of these cells in the course of the degenerative changes and necrosis development that corresponded to the breakdown of the compensatory-adaptive mechanisms in the high proteinuria of a long duration. The signs of the podocyte repair in the period of clinical remission resulting from the prednisolone therapy are described.

Adaptation, Physiological↗
PubMed1986

[Characteristics of the cytoskeleton structure of podocytes in vertebrates].

Using transmission electron microscopy a study was made of the cytoskeleton of the renal glomerulus visceral epithelium cells (-podocytes) in representatives of all classes of vertebrates. An obvious tendency of microtubules in the cytoskeletons of the investigated cells is disclosed. This process is accompanied by the intense intracellular development of microfilaments. The role the podocyte cytoskeleton in renal ultrafiltration, and possible mechanisms of its functioning are discussed.

Amphibians↗
PubMed1984

[Ultrastructure of the contractile apparatus of renal podocytes in vertebrate phylogenesis].

The evolution-determined ultrastructural characteristics were disclosed in the intracellular organization of the microfilaments of the contractile apparatus of renal podocytes in the lower (marine teleosts) and higher (dogs) vertebrates. In podocytes of the renal glomerules of the flounder and flying fish, the microfilaments 8-10 nm thick form dense bundles that make up an integral widely branched system, whereas in dogs, the microfilaments 4-7 nm thick are diffusely distributed in the cytoplasm, forming in essence its matrix.

Animals↗
PubMed1981

Glomerular podocyte cell junctions in nephrotic syndrome. I. Freeze-fracture studies in rat aminonucleoside nephrosis.

Aminonucleoside nephrosis was induced in rats after a single i.p. injection of puromycin aminonucleoside (PAN). Freeze-fracture studies of the glomeruli were done, three, six and ten days after PAN injection. The epithelial filtration slits disappeared six days after PAN injection. On the split plasma membrane of the podocytes three types of cell junctions which apparently were newly formed were seen: 1) single strands (occluding junctions of leaky type); 2) networks of limited extent, composed of strands and particles (maculae occludentes); 3) assemblies of particles or pits (maculae communicantes) connected by single strands. The cell junctions of podocytes were comparable with those found in human nephrotic syndrome. (Kühn et al., 1981).

Animals↗
PubMed1981

Glomerular podocyte cell junctions in nephrotic syndrome. II. Freeze-fracture studies in human nephrotic syndrome.

In six patients with nephrotic syndrome and in two control subjects freeze-fracture studies of isolated glomeruli obtained by needle biopsies were performed. In the nephrotic patients replicas of freeze-fractured podocytes showed an increased number of cell junctions. These were represented by incomplete occluding junctions and communicating junctions (gap junctions). There was morphologically a similarity between the glomerular podocyte cell junctions in human and experimental nephrotic syndrome (Kühn et al., 1981).

Adolescent↗
PubMed1995

[Autoantibodies against podocytes of the kidney glomerulus].

Novel autoantibodies are described which react with renal podocytes. These antibodies were found in 9 patients (2 with renal disease, 2 with liver disease, 2 with rheumatic disease, 1 with achalasia, 1 with carcinoma of the pancreas and 1 with anemia). Colocalization studies with double immunofluorescence and confocal laser scanning microscopy using monoclonal antibodies against the 44 kD podocyte protein showed a similar fluorescence pattern for both antibodies. The target antigens remain unclear.

Adolescent↗
PubMed1994

Diffuse and broad podocytic detachment in a case of nephrotic syndrome associated with Kimura's disease.

We report a 49-year-old Japanese male with nephrotic syndrome associated with Kimura's disease. Renal biopsy revealed diffuse podocytic detachment from the glomerular basement membrane (GBM). He had an episode of nephrotic syndrome when complete remission was induced with steroid therapy six years prior to the present admission. However, complete remission of the nephrotic syndrome was not achieved by the steroid on this admission and massive proteinuria (5 g/day) persisted. We suggest that steroid-resistant proteinuria is closely related to podocytic detachment from the GBM and that the production of extracellular matrix by epithelial cells may participate in segmental sclerotic lesions in the patient.

Angiolymphoid Hyperplasia with Eosinophilia↗