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PubMed2002

Co-localization of nephrin, podocin, and the actin cytoskeleton: evidence for a role in podocyte foot process formation.

The discovery of the genes for nephrin and podocin, which are mutated in two types of congenital nephrotic syndrome, was pivotal in establishing the podocyte as the central component of the glomerular filtration barrier. In vivo the proteins have been localized to the podocyte slit diaphragm, and there is recent evidence for interaction between the two via the adapter molecule CD2AP. We describe in a human podocyte cell line, the subcellular distribution of nephrin, podocins, and CD2AP and their functional interaction with the cytoskeleton. In addition to membrane expression, nephrin and podocin were detected intracellularly in a filamentous pattern. Double immunolabeling and depolymerization studies showed that nephrin and podocin partially co-localize with actin, most strikingly seen protruding from the tips of actin filaments, and are dependent on intact actin polymers for their intracellular distribution. Treatment of differentiated podocytes with puromycin aminonucleoside, an agent that causes foot process effacement in vivo, disrupted actin and nephrin simultaneously, with loss of cell surface localization. We demonstrate an intimate relationship between nephrin podocin and filamentous actin, and reason that disruption of nephrin/podocin could be a final common pathway leading to foot process effacement in proteinuric diseases.

Actins↗
PubMed1999

WT1 and PAX-2 podocyte expression in Denys-Drash syndrome and isolated diffuse mesangial sclerosis.

Denys-Drash syndrome is a rare disorder of urogenital development characterized by the association of early onset glomerulopathy caused by diffuse mesangial sclerosis, gonadal dysgenesis leading to pseudohermaphroditism in males, and a high risk of developing Wilms' tumor. The syndrome is caused by dominant negative point mutations in the WT1 gene that encodes a tumor suppressor transcription factor normally expressed in podocytes. Mutations usually affect the zinc fingers of the WT1 protein. The basic defect is unknown in most cases of isolated diffuse mesangial sclerosis, a disease characterized by the same glomerular changes as in Denys-Drash syndrome but possibly transmitted as an autosomal recessive trait. Here we show that the distribution of WT1 is abnormal in most patients with Denys-Drash syndrome : WT1 nuclear staining of podocytes is decreased or absent. This finding is consistent with the decreased DNA binding capacity of the mutated protein. One target gene of WT1 is PAX2, the expression of which is down-regulated in podocytes during early stages of nephrogenesis. We demonstrate that WT1 mislocalization is associated with abnormal podocyte expression of PAX2 protein and RNA. We suggest that persistent expression of PAX2 is likely to result from the loss of WT1 dependent transcriptional repression and may participate in the pathological mechanisms leading to glomerular dysfunction. Abnormal distribution of WT1 and PAX2 was also observed in isolated diffuse mesangial sclerosis suggesting that a defect in WT1 could also be operative in isolated diffuse mesangial sclerosis. Primary involvement of PAX2 is an alternative hypothesis because persistent expression of PAX2 in transgenic mice is associated with the occurrence of early and severe glomerulopathy.

Animals↗
PubMed2000

Protection of alpha(3) integrin-mediated podocyte shape by superoxide dismutase in the puromycin aminonucleoside nephrosis rat.

Because reactive oxygen species (ROS) are involved in the development of puromycin aminonucleoside nephrosis (PAN), we examined whether superoxide dismutase (SOD) could ameliorate this condition. Phosphatidyl choline-bound SOD (PC-SOD) has higher affinity for the cell membrane than recombinant human SOD (rhSOD). In this study, PC-SOD had a longer half-life in the circulation and also higher affinity to renal fractions (glomerulus, brush border, and tubulus) than rhSOD. PAN was induced in rats with single injections of puromycin aminonucleoside. Rats were divided into four groups: group P, PAN rats without treatment; group PC-T and group rh-T, PAN rats treated with 30,000 U/kg PC-SOD and rhSOD, respectively; and group C, normal controls. The effect of PC-SOD versus rhSOD on PAN was evaluated by morphological podocyte changes (podocyte density along the GBM) and alpha(3) integrin expression at days 4 and 10. Proteinuria was measured over time until day 14. Distribution and quantitation of alpha(3) integrin were studied by confocal laser scan microscopy. On day 4, glomerular ROS was measured by chemiluminescence without stimulation. PC-SOD decreased proteinuria to the control level, but rhSOD only decreased proteinuria by 31%. PC-SOD significantly improved podocyte density (P < 0.05 versus group P). Total alpha(3) integrin expression decreased in the P and rh-T groups at day 4 and then had recovered by day 10, but the polarity of the site of expression did not recover. PC-T preserved both the amount and polarity of integrin expression on days 4 and 10. PC-SOD significantly suppressed ROS generation in PAN (P < 0.05). These findings suggest that alpha(3) integrin regulates glomerular permeability by maintaining podocyte shape and adhesion, which is disrupted by ROS overproduction.

Animals↗
PubMed1975

Focal glomerular sclerosis in nephrotic patients: an electron microscopic study of glomerular podocytes.

Renal biopsy specimens of 16 adult patients with nephrotic syndrome and focal glomerular sclerosis were examined by light and electron microscopy. Particular attention was paid to alterations of podocytes. Except for loss of foot processes, five patients had no podocyte changes, five had mild changes and six had severe changes. Of the last group (group III), four patients were heroin addicts, the fifth had infectious mononucleosis and the sixth, an apparent idiopathic disease; five patients were males, 16 to 25 yr old. Podocyte changes consisted of cytoplasmic degeneration, detachment of epithelial cells from basement membranes, with filling of resulting space by cell debris and new membranes. Underlying capillaries were often collapsed. Repeat biopsies in three patients in group III revealed progression of lesions, paralleling rapid clinical deterioration. It is concluded that some cases of focal glomerular sclerosis are associated with severe damage to podocytes which may be caused by drugs, infection or unknown factors and may contribute to the development and progression of the glomerular lesions.

Adolescent↗
PubMed1996

Structural continuity of filtration slit (slit diaphragm) to plasma membrane of podocyte.

Murine monoclonal antibody 5-1-6 was reported to bind to the slit membrane and closely related structures in rat renal glomeruli; it induced heavy, reversible proteinuria and appeared to redistribute onto the plasma membrane of epithelial cells after binding at the original target sites. This phenomenon of antigenic movement has not been analyzed in detail to date. In addition to normal kidneys we also studied localization of the antigen recognized by monoclonal antibody 5-1-6 in protamine sulfate-perfused rat kidneys, in which slit diaphragms are known to be functionally modified. Isolated glomeruli as well as ultrathin kidney cryosections were labeled by the immunogold technique to clarify the relation between this antigen and the slit diaphragm. Sequential localization of injected monoclonal antibody was visualized using a post-embedding immunogold method in rats 2 hours to 12 days after injection of antibody. Ultrastructural immunogold labeling demonstrated that under normal conditions antigenic molecules were expressed mainly in the area beneath the slit diaphragms. Occasionally labeling was found at the base of the foot process, facing the glomerular basement membrane. After protamine sulfate treatment antigenic sites were dislocated due to the lifting and disruption of slit diaphragms, indicating that this antigen is associated with slit diaphragms. Injected antibody was localized at the filtration slits at 2 hours, and by 12 hours it had moved onto the apical plasma cell membrane of foot process. In addition, from 3 days onwards patch or cap-like formation on the plasma cell membrane of podocytes was seen. Possible shedding of antibody from podocyte cell surface membrane was occasionally encountered, but internalization of antibody was a minor event. Elution experiments in isolated glomeruli at day 3 indicated that antigen and antibody were both localized on the podocyte cell surface membrane, suggesting redistribution of immune complexes. In conclusion, filtration slits (slit diaphragms) and the apical membrane of foot process of podocytes demonstrate structural continuity, as revealed by the movement of the antigen recognized by monoclonal antibody 5-1-6 as antigen-antibody complexes.

Animals↗
PubMed2006

Nck adaptor proteins link nephrin to the actin cytoskeleton of kidney podocytes.

The glomerular filtration barrier in the kidney is formed in part by a specialized intercellular junction known as the slit diaphragm, which connects adjacent actin-based foot processes of kidney epithelial cells (podocytes). Mutations affecting a number of slit diaphragm proteins, including nephrin (encoded by NPHS1), lead to renal disease owing to disruption of the filtration barrier and rearrangement of the actin cytoskeleton, although the molecular basis for this is unclear. Here we show that nephrin selectively binds the Src homology 2 (SH2)/SH3 domain-containing Nck adaptor proteins, which in turn control the podocyte cytoskeleton in vivo. The cytoplasmic tail of nephrin has multiple YDxV sites that form preferred binding motifs for the Nck SH2 domain once phosphorylated by Src-family kinases. We show that this Nck-nephrin interaction is required for nephrin-dependent actin reorganization. Selective deletion of Nck from podocytes of transgenic mice results in defects in the formation of foot processes and in congenital nephrotic syndrome. Together, these findings identify a physiological signalling pathway in which nephrin is linked through phosphotyrosine-based interactions to Nck adaptors, and thus to the underlying actin cytoskeleton in podocytes. Simple and widely expressed SH2/SH3 adaptor proteins can therefore direct the formation of a specialized cellular morphology in vivo.

Actins↗
PubMed1998

Progression of glomerular diseases: is the podocyte the culprit?

The stereotyped development of the glomerular lesions in many animal models and human forms of progressive renal disease suggests that there are common mechanisms of disease progression. We propose the outline of such a mechanism based on following aspects: (1) The glomerulus is a complex structure, the stability of which depends on the cooperative function of the basement membrane, mesangial cells and podocytes, counteracting the distending forces originating from the high glomerular hydrostatic pressures. Failure of this system leads to quite uniform architectural lesions. (2) There is strong evidence that the podocyte is incapable of regenerative replication post-natally; when podocytes are lost for any reason they cannot be replaced by new cells. Loss of podocytes may therefore lead to areas of "bare" GBM. which represent potential starting points for irreversible glomerular injury. (3) Attachment of parietal epithelial cells to bare GBM invariably occurs when bare GBM coexists with architectural lesions, leading to the formation of a tuft adhesion to Bowman's capsule, the first "committed" lesion progressing to segmental sclerosis. (4) Within an adhesion the tuft merges with the interstitium, allowing filtration from perfused capillaries inside the adhesion towards the interstitium. The relevance of such filtration is as yet unclear but may play a considerable role in progression to global sclerosis and interstitial fibrosis.

Humans↗
PubMed1998

Analysis of mouse glomerular podocyte mRNA by single-cell reverse transcription-polymerase chain reaction.

Selective investigation of glomerular podocytes is not possible using conventional methods in vivo. Analysis of glomerular epithelium-derived cells in culture yields dubious results because of the rapid dedifferentiation of podocytes. We developed a modification of the polymerase chain reaction (PCR) method previously used to analyze cultured neurons. Podocytes harvested from freshly dissected glomeruli are ideal target cells for this modified, single cell reverse transcription-PCR method to reproducibly identify specific mRNA species from resident intact podocytes in vivo.

Actins↗
PubMed2004

Cell-cycle mechanisms involved in podocyte proliferation in cellular lesion of focal segmental glomerulosclerosis.

BACKGROUND: Podocyte injury may induce podocyte proliferation, which results in glomerular scarring. The cellular lesion, seen in some patients with primary focal segmental glomerulosclerosis (FSGS), is characterized by proliferation of cells covering the sclerotic or collapsed glomerular tufts. Cell-cycle mechanisms by which podocyte proliferation occurs in the cellular lesion of FSGS are unclear. METHODS: We examined expression patterns of cyclin D1; cyclin E; cyclin A; cyclin B1; cyclin-dependent kinase (CDK)2; CDK4; such CDK inhibitors as p21WAF1/CIP1 (p21), p27kip1 (p27), and p57kip2 (p57); and Wilms' tumor protein-1 (WT-1) in 12 renal biopsy specimens with the cellular lesion of FSGS and 6 renal biopsy specimens with no detectable abnormalities by immunohistochemistry and immunoelectron microscopy. Messenger RNA (mRNA) expression patterns of cyclin D1, cyclin E, p21, p27, and p57 were evaluated further by in situ hybridization. RESULTS: In controls, immunostaining for cyclin A, cyclin B1, CDK2, CDK4, and p21 was almost negligible, but positive signals for cyclin D1, cyclin E, p27, and p57 were observed in glomerular epithelial cells (GECs). In the cellular lesion of FSGS, positive signals for cyclin E, cyclin A, cyclin B1, CDK2, and p21 were present in GEC nuclei, in which WT-1, p27, p57, and cyclin D1 were undetected. Immunoelectron microscopy showed that cyclin E-, CDK2-, and p21-specific gold particles were increased significantly in GEC nuclei in the cellular lesion in which cyclin D- and p57-specific particles were absent compared with controls. An in situ hybridization study showed specific signals of cyclin D1, cyclin E, p21, p27, and p57 mRNA in GECs forming the cellular lesion of FSGS. CONCLUSION: Our results suggest that damaged podocytes may inhibit p27 and p57 protein expression, but activate a cyclin D1-independent cell-cycle mechanism and mitotic cell cyclins to promote GEC proliferation in the cellular lesion of FSGS.

Adult↗
PubMed2005

Effect of low-density lipoprotein apheresis on urinary protein and podocyte excretion in patients with nephrotic syndrome due to diabetic nephropathy.

BACKGROUND: The aim of the present study is to determine whether low-density lipoprotein (LDL) apheresis affects proteinuria and urinary podocyte excretion in patients with type 2 diabetes and nephrotic syndrome. METHODS: LDL apheresis was performed on patients with diabetes with long-standing nephrotic syndrome, and urinary protein level and number of urinary podocytes were compared between these patients (5 men, 3 women; mean age, 54.6 years) and 10 nephrotic patients with diabetes not treated with LDL apheresis (6 men, 4 women; mean age, 56.5 years). RESULTS: LDL apheresis reduced total cholesterol (P < 0.001), LDL cholesterol ( P < 0.001), lipoprotein(a) (P < 0.001), creatinine (P < 0.05), and blood urea nitrogen (P < 0.05) levels and increased creatinine clearance (P < 0.05). The LDL apheresis group showed a significant decrease in urinary protein excretion (from 10.8 +/- 3.2 to 1.8 +/- 1.1 g/d; P < 0.001) and number of urinary podocytes (from 4.8 +/- 2.2 to 0.9 +/- 0.4 cells/mL; P < 0.01). CONCLUSION: These data suggest that LDL apheresis effectively reduces proteinuria and podocyte excretion, ameliorating renal dysfunction in patients with nephrotic syndrome caused by diabetic nephropathy.

Adult↗
PubMed2005

CD2-associated protein (CD2AP) expression in podocytes rescues lethality of CD2AP deficiency.

Mice born without CD2-associated protein (CD2AP) develop renal failure and nephrotic syndrome about 4 weeks after birth and die around 6 weeks of age. Although CD2AP is widely expressed, the severity of the renal failure precludes a clear determination of the role of CD2AP in other tissues. Here we generated transgenic mice expressing CD2AP using a podocyte-specific promoter. Podocyte-specific expression of CD2AP prevented the development of proteinuria, demonstrating that the renal failure is solely due to loss of CD2AP in podocytes and not in other renal or in immune cells. CD2AP-deficient mice are long-lived and appear phenotypically normal. Histological analysis demonstrated testicular abnormalities that were age-related. CIN85, a paralog of CD2AP, is poorly expressed in both the podocyte and the basal seminiferous tubule, suggesting that the loss of CD2AP in specific tissues may be compensated for by CIN85.

Adaptor Proteins, Signal Transducing↗
PubMed2002

WT1 is a key regulator of podocyte function: reduced expression levels cause crescentic glomerulonephritis and mesangial sclerosis.

Glomerular disease is one of the most common causes of end-stage renal failure. Increasing evidence suggests that these glomerulopathies are frequently caused by primary lesions in the renal podocytes. One of the major consequences of podocyte lesions is the accumulation of mesangial matrix in the glomerular basement membrane, a process called glomerulosclerosis. Mesangial sclerosis is one of the most consistent findings in Denys-Drash patients and can be caused by dominant mutations in the Wilms' tumor 1 gene (WT1). The underlying mechanism, however, is poorly understood. WT1 is expressed in the podocytes throughout life, but its function in this cell type is unknown. Combining Wt1-knockout and inducible yeast artificial chromosome transgenic mouse models, we demonstrate that reduced expression levels of WT1 result in either crescentic glomerulonephritis or mesangial sclerosis depending on the gene dosage. Strikingly, the two podocyte-specific genes nphs1 and podocalyxin are dramatically downregulated in mice with decreased levels of Wt1, suggesting that these two genes act downstream of Wt1. Taken together, our data provide genetic evidence that reduced levels of Wt1 are responsible for the pathogenesis of two distinct renal diseases and offer a molecular explanation for the increased occurrence of glomerulosclerosis in patients with WAGR syndrome.

Animals↗
PubMed2002

Glomerular podocyte endocytosis of the diabetic rat.

We used immunoelectron microscopy to examine whether glomerular podocytes have the endocytotic function of macromolecular proteins in the early stage of diabetic nephropathy. Diabetes was induced by injecting streptozocin 60 mg kg wt(-1) into rats. Creatinine clearance but not urinary protein excretion was increased after four weeks of diabetes. The kidneys were morphologically studied 1 h after goat serum injection. In conventional electron microscopy, lysosomes were conspicuous in the podocytes of diabetic rats. Immunoelectron microscopy revealed that endogenous rat IgG and exogenous goat IgG were present in the lysosomes of podocytes from diabetic rats. The results indicated that the podocytes had an increased capacity for endocytosis in the early stage of diabetic nephropathy without increased urinary protein excretion.

Animals↗
PubMed2003

Podocyte proliferation and differentiation in glomerular disease: role of cell-cycle regulatory proteins.

Injury to the podocyte underlies many forms of glomerular disease. In contrast to mesangial and endothelial cells, podocytes do not typically proliferate. Moreover, the lack of proliferation is thought to underlie the development of glomerulosclerosis. Studies have recently shown that the lack of podocyte proliferation is due to an increase in cyclin-dependent kinase inhibitors, which arrest the cell cycle. Current work is aimed at further delineating the mechanisms regulating podocyte proliferation.

Cell Cycle↗
PubMed2003

Focal and segmental glomerulosclerosis in mice with podocyte-specific expression of mutant alpha-actinin-4.

Mutations in the gene encoding alpha-actinin-4 (ACTN4), an actin crosslinking protein, are associated with a form of autosomal dominant focal segmental glomerulosclerosis (FSGS). To better study its progression, a transgenic mouse model was developed by expressing murine alpha-actinin-4 containing a mutation analogous to that affecting a human FSGS family in a podocyte-specific manner using the murine nephrin promoter. Consistent with human ACTN4-associated FSGS, which shows incomplete penetrance, a proportion of the transgenic mice exhibited significant albuminuria (8 of 18), while the overall average systolic BP was elevated in both proteinuric and non-proteinuric ACTN4-mutant mice. Immunofluorescence confirmed podocyte-specific expression of mutant alpha-actinin-4, and real-time RT-PCR revealed that HA-ACTN4 mRNA levels were higher in proteinuric versus non-proteinuric ACTN4-mutant mice. Only proteinuric mice exhibited histologic features consistent with human ACTN4-associated FSGS, including segmental sclerosis and tuft adhesion of some glomeruli, tubular dilatation, mesangial matrix expansion, as well as regions of podocyte vacuolization and foot process fusion. Consistent with such podocyte damage, proteinuric ACTN4-mutant kidneys exhibited significantly reduced mRNA and protein levels of the slit diaphragm component, nephrin. This newly developed mouse model of human ACTN4-associated FSGS suggests a cause-and-effect relationship between actin cytoskeleton dysregulation by mutant alpha-actinin-4 and the deterioration of the nephrin-supported slit diaphragm complex.

Actin Cytoskeleton↗
PubMed2003

Cell biological and biochemical characterization of drebrin complexes in mesangial cells and podocytes of renal glomeruli.

Drebrins are actin-binding proteins (ABP) initially identified in and thought to be specific for neuronal cells, where they appear to contribute to the formation of cell processes. Recent studies have also detected the isoform drebrin E2 in a wide range of non-neuronal cell types, notably in and near actin-rich lamellipodia and filopodia. The present study demonstrates drebrin enrichment in renal glomeruli. Immunohistochemistry and double-label confocal laser scanning microscopy have shown intense drebrin reactions in the mesangial cells of diverse mammalian species. In adult human and bovine kidneys, drebrin is, in addition, markedly enriched in the foot processes of podocytes, as also demonstrable by immunoelectron microscopy. By contrast, the podocytes of rodent glomeruli appear to contain significant drebrin concentrations only during early developmental stages. In differentiated murine podocytes cultured in vitro, however, drebrin is concentrated in the cell processes, where it partially codistributes with actin and other ABP. In biochemical analyses using protein extracts from renal cortices, large (approximately 20S) complexes ("drebrosomes") were found containing drebrin and actin. These findings confirm and extend our hypothesis that drebrin is involved in the regulation of actin dynamics also outside the nervous system. Clearly, drebrin has to be added to the ensemble of ABP regulating the actomyosin system and the dynamics of mesangial cells and foot processes in podocytes.

Animals↗
PubMed2004

Angiotensin II type 1-receptor mediated changes in heparan sulfate proteoglycans in human SV40 transformed podocytes.

In patients with diabetic nephropathy, glomerular staining for heparan sulfate proteoglycans (HSPG) side chains and for agrin is decreased. In the present study, the influence of angiotensin II (AngII) on the production of HSPG in SV40 transformed podocytes was investigated. SV40 transformed human podocytes were cultivated with or without 1 microM AngII, and HSPG production was measured by sequential DEAE-anion exchange chromatography and HPLC-DEAE separation. Expression of agrin was studied by indirect immunofluorescence and Western blot analysis using specific mono- and polyclonal antibodies. DEAE separation of total glycosaminoglycans (GAG) revealed a significant increase of GAG in the culture supernatant and decrease in the cell and matrix layer when podocytes were cultured for 72 h in the presence of AngII. This was particularly found for HS-GAG. Qualitative analysis of HSPG, using gel filtration of HNO(2)-treated fractions, showed that AngII treatment decreased N-sulfation of HS-GAG side chains. Indirect immunofluorescence staining with anti-agrin polyclonal antibody was strongly decreased after AngII stimulation. A reduction in agrin expression in cell extracts could also be detected in Western blot analysis using an mAb. No changes in agrin mRNA were found after AngII stimulation. It is concluded from this study that AngII decreases the amount of HSPG on the cell surface and in the extracellular matrix of podocytes. Because HSPG play a fundamental role in the permselectivity of the glomerular basement membrane, these results thus may explain at least partially the antiproteinuric effects of angiotensin-converting enzyme inhibition in patients with diabetic nephropathy.

Agrin↗
PubMed2004

Downregulation of Bcl-2 by podocytes is associated with progressive glomerular injury and clinical indices of poor renal prognosis in human IgA nephropathy.

Bcl-2 defines a new class of proto-oncogenes that block cell death without promoting cell proliferation. To elucidate the role of Bcl-2 in the development of glomerular lesions in human IgA nephropathy (IgAN), we applied immunohistochemistry coupled with in situ hybridization to detect the expression of Bcl-2 products and their association with Bax, p27(kip1), and p57(kip2) in modulating the apoptotic, proliferative, and sclerotic events in progressive glomerular injury. Glomerular cell apoptosis was examined by TdT-mediated dUTP-biotin nick-end labeling (TUNEL) staining. A total of 51 IgAN cases were categorized into four subgroups (A to D) according to the severity of their histopathological lesions. Creatinine levels, creatinine clearance, and magnitude of proteinuria based on 24-h urine collections at the time of diagnostic renal biopsy were available for the majority of subjects. Bcl-2 expression was observed predominantly in podocytes in IgAN. Podocyte expression of Bcl-2 was found to be upregulated in early-stage disease and downregulated in late-stage disease. Bcl-2 downregulation in progressive IgAN was associated with an increased Bax/Bcl-2 ratio in glomerular epithelial cells and correlated with the downregulation of high endogenous podocyte p27(kip1) and p57(kip2) expression. Bax/Bcl-2 ratios positively correlated with glomerular cell apoptosis and the degree of glomerulosclerosis, whereas p27(kip1) and p57(kip2) expression levels were inversely correlated with mesangial hypercellularity and glomerulosclerosis. Clinicopathologic correlations demonstrated that downregulation of Bcl-2 protein expression was associated with indices of poor renal prognosis in human IgAN. The results suggest that Bcl-2 expression by podocytes may exert modulatory effects on cellular processes that contribute to progressive glomerular injury and play an important role in determining renal outcome in human IgA nephropathy.

Adolescent↗