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PubMed2001

WT1 regulates the expression of the major glomerular podocyte membrane protein Podocalyxin.

The WT1 tumor suppressor gene encodes a zinc finger transcription factor expressed in differentiating glomerular podocytes. Complete inactivation of WT1 in the mouse leads to failure of mesenchymal induction and renal agenesis, an early developmental phenotype that prevents analysis of subsequent stages in glomerular differentiation [1]. In humans with Denys-Drash Syndrome, a heterozygous germline mutation in WT1 is associated with specific defects in glomeruli and an increased risk for developing Wilms Tumor [2,3]. WT1 target genes implicated in cell cycle regulation and cellular proliferation have been proposed [4], but the link between WT1 function and glomerular differentiation is unexplained. Here, we show that inducible expression of WT1 in rat embryonic kidney cell precursors leads to the induction of endogenous Podocalyxin, the major structural membrane protein of glomerular podocytes, which is implicated in the maintenance of filtration slits. Binding of WT1 to conserved elements within the Podocalyxin gene promoter results in potent transcriptional activation, and the specific expression pattern of Podocalyxin in the developing kidney mirrors that of WT1 itself. These observations support a role for WT1 in the specific activation of a glomerular differentiation program in renal precursors and provide a molecular basis for the glomerulonephropathy that is characteristic of Denys-Drash Syndrome.

3T3 Cells↗

PubMed1994

A role for podocytes to counteract capillary wall distension.

In a previous study of the changes in glomerular structure in the isolated perfused kidney (IPK), perfusion at high pressures lead to an enlargement of the glomerular tuft and to the formation of giant capillaries. The present paper analyzes the morphological and dimensional changes of the peripheral glomerular capillary wall under these circumstances. The enlargement of glomerular capillaries at high pressure perfusion was accompanied by a considerable increase in the surface area of the glomerular basement membrane (GBM). The podocyte as well as the endothelial layer perfectly adapted to the acute challenge in covering increasing GBM area. The interdigitating foot process pattern showed up in an ideal arrangement. The capillary wall expansion was associated with a significant increase in total pericapillary slit area. Compared to the corresponding low pressure groups (65 mm Hg, without and with the application of vasodilators) the slit area increased in the high pressure groups (105 mm Hg, without and with vasodilator) by approximately 50 and 75%, respectively. This increase of the slit area was mainly due to an increase in slit length; the slit width remained fairly constant. These findings indicate that the pericapillary wall is distensible based on a distensibility of the GBM. We suggest that the contractile apparatus of podocyte foot processes regulates the expansion of the GBM.

Animals↗

PubMed1997

Age-related glomerulosclerosis and interstitial fibrosis in Milan normotensive rats: a podocyte disease.

In Milan normotensive (MNS) rats glomerulosclerosis and interstitial fibrosis develop spontaneously in the absence of hypertension. Renal changes were sequentially assessed in these rats between 2 and 10 months of age. At 10 months, rats were characterized by heavy proteinuria, increased serum creatinine, focal or global glomerulosclerosis in 51 +/- 12% of the glomeruli as well as tubulointerstitial injury involving > 25% of the section area. Cell injury in podocytes (evidenced as increased expression of desmin and by electron microscopy) and interstitial fibroblasts (increased expression of alpha-smooth muscle actin) and mild glomerular hypertrophy were witnessed as early as three to four months of age and preceded glomerulosclerosis and interstitial fibrosis. Only minor evidence of mesangial cell activation (as assessed by glomerular (de novo alpha-smooth muscle actin or type I collagen expression or increased cell proliferation) was noted throughout the observation period. Later stages of the disease were characterized by glomerular and/or tubulointerstitial macrophage influx and osteopontin expression (a chemoattractant), mild accumulation of lymphocytes, platelets, fibrinogen, as well as by a progressive accumulation of various matrix proteins. Progressive renal disease in MNS rats is thus noteworthy for the relative lack of mesangial cell activation. Rather, early podocyte damage, induced by yet unknown mechanisms, may underlie the development of glomerulosclerosis and subsequent interstitial fibrosis.

Actins↗

PubMed2004

Fabry disease: renal involvement limited to podocyte pathology and proteinuria in a septuagenarian cardiac variant. Pathologic and therapeutic implications.

In men with classical Fabry disease (alpha-galactosidase A [alpha-Gal A] deficiency), kidney failure occurs as early as the second decade of life. In contrast, men with the mild "cardiac variant" have late-onset cardiac involvement and proteinuria but usually do not have renal failure. To investigate the nature of renal involvement in the cardiac variant of Fabry disease, the renal function and morphology were assessed in a 75-year-old affected man. He had mild congestive heart failure, a reduced left ventricular ejection fraction, and hypercholesterolemia but lacked the classical Fabry disease manifestations, including angiokeratoma, acroparesthesias, corneal and lenticular opacities, and hypohidrosis. At age 75 years, he had significant proteinuria, and mildly decreased renal function (serum creatinine, 1.8 mg/dL [159 micromol/L]), presumably secondary to hypertensive arteriosclerosis. He had about 4% residual alpha-Gal A activity in leukocytes, and mutation analysis identified the N215S missense mutation, the common lesion in cardiac variants. Histologic and ultrastructural studies of kidney tissue showed that lysosomal glycosphingolipid deposition was extensive in podocytes, rare in tubular epithelial cells, and absent in mesangial, interstitial, and vascular endothelial and smooth muscle cells. This cardiac variant serves as an "experiment of nature" showing that the residual alpha-Gal A activity precludes glycosphingolipid deposition in the renal endothelial and other cells that lead to early renal failure in classically affected men, whereas marked podocyte accumulation is associated with proteinuria and possibly late-onset renal dysfunction. These findings have important implications for the renal effectiveness of enzyme replacement therapy in classically affected patients and for the aggressive treatment of proteinuria in Fabry disease.

Aged↗

PubMed2001

Diabetogenic transferrin damages podocytes in early human diabetic nephropathy.

The exact mechanisms by which growth hormone (GH) damages the kidney inducing diabetic nephropathy has not yet been elucidated. Recently, it has been shown that transferrin has the same diabetogenic effects of GH, being its mediator. Transferrin was studied using immunohistochemistry and immunoelectron microscopy in cases of early diabetic nephropathy, and in controls. Transferrin was only found in diabetic cases in podocytes and Bowman's capsule cells, but also in the tubular cells of both diabetic and non-diabetic controls. Immuno-electron microscopy for the presence of transferrin showed positive signals in the cytoplasm of diabetic podocytes, but not in pedicels. This selective deposition was associated with signs of organelle and cytoskeleton damage. On the basis of previous evidence and present glomerular findings, these results suggest an indirect diabetogenic effect on the kidney by GH mediated through transferrin.

Adult↗

PubMed1985

Localization of sialic acid in kidney glomeruli: regionalization in the podocyte plasma membrane and loss in experimental nephrosis.

Sialic acid residues were localized by electron microscopy in renal glomeruli of normal and puromycin-treated rats with a cytochemical technique that utilized the Limax flavus lectin. In Lowicryl K4M thin sections from normal rats, sialic acid residues were found along the plasma membrane of the various glomerular cell types and in the glomerular basement membrane as well as the mesangial matrix. In NaDodSO4/PAGE, sialic acid residues of normal glomeruli were mainly confined to a 140-kDa protein previously identified as podocalyxin. The distribution of sialic acid residues in the podocyte plasma membrane was found to be remarkably regionalized. Based on the differential labeling intensity, three plasma membrane domains could be defined: the foot process base, the foot process region above the slit diaphragm, and the body of podocytes. Cytochemical and biochemical analysis of glomeruli from puromycin-treated rats showed a loss of sialic acid residues from glomerular sialoglycoconjugates indicating a perturbated glycosylation.

Animals↗

PubMed1997

Synaptopodin: an actin-associated protein in telencephalic dendrites and renal podocytes.

Synaptopodin is an actin-associated protein of differentiated podocytes that also occurs as part of the actin cytoskeleton of postsynaptic densities (PSD) and associated dendritic spines in a subpopulation of exclusively telencephalic synapses. Amino acid sequences determined in purified rat kidney and forebrain synaptopodin and derived from human and mouse brain cDNA clones show no significant homology to any known protein. In particular, synaptopodin does not contain functional domains found in receptor-clustering PSD proteins. The open reading frame of synaptopodin encodes a polypeptide with a calculated Mr of 73.7 kD (human)/74.0 kD (mouse) and an isoelectric point of 9.38 (human)/9. 27 (mouse). Synaptopodin contains a high amount of proline ( approximately 20%) equally distributed along the protein, thus virtually excluding the formation of any globular domain. Sequence comparison between human and mouse synaptopodin revealed 84% identity at the protein level. In both brain and kidney, in vivo and in vitro, synaptopodin gene expression is differentiation dependent. During postnatal maturation of rat brain, synaptopodin is first detected by Western blot analysis at day 15 and reaches maximum expression in the adult animal. The exclusive synaptopodin synthesis in the telencephalon has been confirmed by in situ hybridization, where synaptopodin mRNA is only found in perikarya of the olfactory bulb, cerebral cortex, striatum, and hippocampus, i.e., the expression is restricted to areas of high synaptic plasticity. From these results and experiments with cultured cells we conclude that synaptopodin represents a novel kind of proline-rich, actin-associated protein that may play a role in modulating actin-based shape and motility of dendritic spines and podocyte foot processes.

Actins↗

PubMed1993

The detection of CR1 mRNA and CR1 antigen identifies the presence of immature podocytes in a case of Wilms' tumor (nephroblastoma).

Wilms' tumors (nephroblastomas) are heterogeneous tumors consisting of proliferating epithelial cells in glomeruloid bodies and tubule formations and of proliferating blastemal cells. Using a specific CR1 35S-labeled cDNA probe and CR1 antibodies, CR1 mRNA and CR1 antigen-expressing cells were detected in glomeruloid bodies in one case of Wilm's tumor. The concomitant expression of CR1 mRNA and CR1 antigen and the high level of CR1 mRNA expression that characterize podocytes at an early stage of glomerular maturation in the normal human fetal kidneys indicates that glomeruloid bodies are composed of immature podocytes.

DNA Probes↗

PubMed1999

Visualization of the interaction between blood vessels and podocytes in the mouse embryonic glomerulus using a barium-infusion method for scanning electron microscopy.

The present study revealed three dimensionally the formation of epithelial cells and vascular capillaries in glomeruli of the kidney of the mouse embryo. Barium sulphate was infused through the umbilical vessel of 16.5-17.5-day embryos and the backscattered electron (BSE) image and the secondary electron (SE) image of the identical area of glomeruli were obtained by scanning electron microscopy (SEM). The BSE images directly showed the vascular structure of the glomerulus, while the SE images showed a developmental process of podocytes from epithelial cells. Podocytes were more closely located to the vascular capillary than other epithelial cells. These findings were compared with those obtained in the resin cast model of glomeruli. Thus, the metal infusion-SEM method described here can trace the process of formation of urine filtration barrier in the mouse embryonic glomerulus.

Animals↗

PubMed1992

Functional endothelin 1 receptors on human glomerular podocytes and mesangial cells.

To determine if endothelin 1 (Et1) receptors are present in human glomeruli, and which glomerular cells possess these receptors, 125I Et1 binding to isolated glomeruli and cultured glomerular mesangial and epithelial cells was studied. The latter were identified as podocytes. We demonstrated that Et1 binds specifically and reversibly to isolated human glomeruli and to cultured glomerular mesangial and epithelial cells. Scatchard analysis of competitive inhibition of 125I Et1 binding gave the following results (m +/- SEM, n = 3): isolated glomeruli, Kd = 4.2 +/- 2.1 x 10(-10) M, Bmax = 8.1 +/- 1.2 x 10(10) sites/mg protein; mesangial cells, Kd = 5.2 +/- 1.5 x 10(-10) M, Bmax = 1.87 +/- 0.49 x 10(4) sites/cell; epithelial cells, Kd = 7.2 +/- 1.5 x 10(-10) M, Bmax = 2.46 +/- 0.15 x 10(4) sites/cell. These receptors seem to be functional, since in both mesangial and epithelial cells Et1 induces a rapid and transient increase in intracellular [Ca2+]i. All these results indicate that Et1 may regulate glomerular filtration rate through an autocrine-paracrine pathway on mesangial cells and on podocytes.

Calcium↗

PubMed1999

The role of the podocyte in glomerulosclerosis.

Focal segmental glomerulosclerosis is a pathological hallmark of many forms of progressive renal disease. The 'classic' lesion, based on the adhesion of the capillary tuft to Bowman's capsule, results from the loss of podocytes from the capillary basement membrane. The recently described 'collapsing' variant, in contrast, has an apparent excess of extracapillary cells, which may represent dedifferentiated, 'dysregulated' podocytes.

Animals↗

PubMed2003

Podocyte differentiation and hereditary proteinuria/nephrotic syndromes.

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

Animals↗

PubMed2003

Gene expression profiles of podocyte-associated molecules as diagnostic markers in acquired proteinuric diseases.

For identifying potential diagnostic markers of proteinuric glomerulopathies, glomerular mRNA levels of molecules relevant for podocyte function (alpha-actinin-4, glomerular epithelial protein 1, Wilms tumor antigen 1, synaptopodin, dystroglycan, nephrin, podoplanin, and podocin) were determined by quantitative real-time RT-PCR from microdissected glomeruli. Biopsies from 83 patients with acquired proteinuric diseases were analyzed (minimal change disease [MCD; n = 13], benign nephrosclerosis [n = 16], membranous glomerulopathy [n = 31], focal and segmental glomerulosclerosis [FSGS; n = 9], and controls [n = 14]). Gene expression levels normalized to two different housekeeping transcripts (glyceraldehyde-3-phosphate-dehydrogenase and 18 S rRNA) did not allow a separation between proteinuric disease categories. However, a significant positive correlation between alpha-actinin-4, glomerular epithelial protein 1, synaptopodin, dystroglycan, Wilms tumor antigen 1, and nephrin was found in all analyzed glomeruli, whereas podocin mRNA expression did not correlate. Because varying amounts of housekeeper cDNA per glomerulus can confound expression ratios relevant for a subpopulation of cells, an "in silico" microdissection was performed using a podocyte-specific cDNA as a reference gene. Expression ratio of podocin to synaptopodin, the two genes with the most disparate expression, allowed a robust separation of FSGS from MCD and nephrosclerosis. Segregation of FSGS from MCD via this ratio was confirmed in an independent population of formaldehyde-fixed archival biopsies (MCD, n = 5; FSGS, n = 4) after glomerular laser capture microdissection. In addition, the expression marker was able to predict steroid responsiveness in diagnostically challenging cases of MCD versus FSGS (n = 6). As the above approach can be performed as an add-on diagnostic tool, these molecular diagnostic parameters could give novel information for the management of proteinuric diseases.

Actinin↗

PubMed2002

Podocyte-associated molecules in puromycin aminonucleoside nephrosis of the rat.

Molecules of central functional significance for the glomerular podocytes are rapidly emerging and have been shown to be distinctly involved in diseases with altered glomerular filtration barrier. Here we used the puromycin aminonucleoside (PA) nephrosis model in the rat to study some key proteins associated with the maintenance of the functional glomerular filtration barrier in vivo. The molecules studied included the filtration slit component nephrin, the hairpin-like membrane protein podocin, the basolateral adhesion molecules beta1 integrin and alpha-dystroglycan, and the cytoskeleton-linking intermediary beta-catenin and the actin-associated alpha-actinin-4. The results showed diminished protein levels of podocin and nephrin in the PA-treated group. beta-catenin showed distinct down-regulation at 3 days of induction, and the control level was reached at 10 days. beta1 integrin was markedly up-regulated during induction. alpha-actinin-4 was not changed at the studied time points. The results show distinct differences in the different domains of podocytes during PA-induced proteinuria.

Actinin↗

PubMed1995

Interferon-gamma (IFN-gamma) and IL-4 expressed during mercury-induced membranous nephropathy are toxic for cultured podocytes.

The subepithelial immune deposits of Dorus Zadel Black (DZB) rats with mercury-induced membranous nephropathy consist of autoantibodies directed to laminin P1 and of complement. The animals develop massive proteinuria within 10-14 days which is associated with obliteration of foot processes of glomerular visceral epithelial cells (GVEC), or podocytes. Previous studies indicate that these autoantibodies are probably not the sole mediator of proteinuria and GVEC damage. In this study we investigated whether circulating or macrophage-derived cytokines can contribute to the GVEC changes as detected in vivo. In vivo at the height of the proteinuria, increased intraglomerular IFN-gamma immunoreactivity was found. In diseased rats a five-fold increase in intraglomerular macrophages was found, but we could not detect intraglomerular IFN-alpha, IFN-beta, IL-1 beta or tumour necrosis factor-alpha (TNF-alpha) by using immunohistology. Subsequently, we exposed cultured GVEC to these cytokines to investigate their cytotoxic effects on several physiological and structural parameters. IFN-gamma and IL-4 were the only cytokines that exerted toxic effects, resulting in a rapidly decreased transepithelial resistance of confluent monolayers, which was closely associated with altered immunoreactivity of the tight junction protein ZO-1. IL-4 also affected vimentin and laminin immunoreactivity. IFN-gamma and IL-4 only interfered with monolayer integrity when added to the basolateral side of the GVEC, indicating specific (receptor-mediated) effects. Only IL-4 decreased the viability of the cells, and treated monolayers demonstrated an increased passage of the 44-kD protein horseradish peroxidase. From our experiments we concluded that IFN-gamma subtly affected monolayer integrity at the level of the tight junctions, and that IL-4 additionally induced cell death. We hypothesize that the toxic effects of the cytokines IFN-gamma and IL-4 as seen with cultured podocytes are necessary together with the autoantibodies, for the ultimate induction of proteinuria in mercury nephropathy in the DZB rat.

Animals↗

PubMed2004

Podocyte injury associated glomerulopathies induced by pamidronate.

BACKGROUND: Pamidronate has been demonstrated to decrease bone-related complications in multiple myeloma and delay progression of the disease. This has led to its use in supportive and maintenance therapy of myeloma in conjunction with steroids and chemotherapy. It has also been selectively used in patients with breast cancer and other neoplasms. METHODS: We report on five patients who developed glomerular disease induced by pamidronate. Pamidronate was the only drug common to all patients. Tests for hepatitis B and C and human immunodeficiency virus (HIV) were negative for all patients. The first two patients received a high dose of pamidronate for 8 weeks, whereas the other three patients were on monthly therapy for a prolonged period of time. Sources of data included chart review and pathologic analysis of kidney biopsy. RESULTS: Three patients were female and two were males and all were Caucasian, ranging in age from 58 to 71 years. Renal biopsy findings included minimal change disease in two, focal segmental glomerulosclerosis in two, and collapsing focal segmental glomerulosclerosis in one. Immunofluorescence was essentially negative in all cases. Electron microscopy showed variable podocyte injury and extensive foot process effacement. There was no evidence of multiple myeloma-related renal disease. After the biopsy, pamidronate was discontinued and renal function stabilized in all patients except the one with the collapsing variant of focal segmental glomerulosclerosis who required hemodialysis. Three patients had resolution of proteinuria, one patient continued to have proteinuria without deterioration in renal function. CONCLUSION: Pamidronate has been mainly associated with collapsing focal segmental glomerulosclerosis. This report expands that relationship and adds other glomerular diseases linked with podocyte injury. Additional studies are needed to define the cause of the variability of renal histology with this agent.

Aged↗

PubMed2005

An efficient system for tissue-specific overexpression of transgenes in podocytes in vivo.

The utility of promoter fragments isolated from the 5'-flanking region of endogenous mammalian genes to drive transgene expression in vivo is often limited by low expression levels. In this study, a bigenic system was established that allows constitutive overexpression of transgenes in a tissue-specific fashion in transgenic mice in a time- and cost-effective fashion. A modified floxed expression vector was constructed [CMVflox-enhanced green fluorescent protein (eGFP)], in which a lacZ cassette (beta-galactosidase) flanked by lox sites was placed between a CMV-promoter and the transgene of interest (eGFP). Before Cre recombination, expression of eGFP was effectively prevented by the interposed floxed lacZ cassette, whereas beta-galactosidase was strongly expressed in transiently transfected cells. Transcription of the gene of interest (eGFP) could be irreversibly activated by cotransfection with Cre recombinase. Mice transgenic for CMVflox-eGFP were generated by pronuclear injection. A rapid assay was developed to identify transgenic founders with active transgene expression by measuring transgene activity (beta-galactosidase) in tail biopsies. Transgene activity in tails correlated with transgene expression in most other tissues tested including podocytes within the kidney. To activate expression of the gene of interest in a tissue-specific fashion, founder mice were mated to the Cre mouse line 2.5P-Cre previously shown to mediate 100% Cre recombination exclusively in podocytes (Moeller MJ, Sanden SK, Soofi A, Wiggins RC, and Holzman LB. Genesis 35: 39-42, 2003). In doubly transgenic offspring, high-level eGFP expression resulting from Cre excision of the interposed lacZ cassette was detected in four of seven CMVflox-eGFP founder lines. This approach should also circumvent common limitations arising from lethality or transgene silencing as a consequence of transgene overexpression.

Animals↗

PubMed2001

Unraveling the molecular make-up of the glomerular podocyte slit diaphragm.

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

Adaptor Proteins, Signal Transducing↗