scholarly journals Expression of Nephrin in Pediatric Kidney Diseases

2001 ◽  
Vol 12 (2) ◽  
pp. 289-296
Author(s):  
JAAKKO PATRAKKA ◽  
VESA RUOTSALAINEN ◽  
ILKKA KETOLA ◽  
CHRISTER HOLMBERG ◽  
MARKKU HEIKINHEIMO ◽  
...  
Keyword(s):  
Focal Segmental Glomerulosclerosis ◽  
Membranous Nephropathy ◽  
Staining Pattern ◽  
Kidney Diseases ◽  
Minimal Change ◽  
Slit Diaphragm ◽  
Segmental Glomerulosclerosis ◽  
Minimal Change Nephrosis ◽  
Pediatric Kidney Diseases

Abstract. Nephrin is a podocyte cell adhesion protein located at the slit diaphragm area of the kidney glomerulus. Mutations in the nephrin gene (NPHS1) lead to congenital nephrosis, suggesting that nephrin is essential for the glomerular filtration barrier. This prompted this study of the expression of nephrin in acquired pediatric kidney diseases usingin situhybridization and immunohistochemistry.In situhybridization for nephrin mRNA was performed in biopsy samples from patients with proteinuria caused by minimal change nephrosis, focal segmental glomerulosclerosis, and membranous nephropathy. The expression of nephrin mRNA was evaluated by grading the signal intensity visually and by counting the number of grains in separate glomeruli. No significant difference was observed in these samples as compared with controls. Immunostaining for nephrin was performed using antibodies directed against extra- and intracellular parts of the molecule. Nephrin staining gave a linear pattern along the glomerular capillary loops. In minimal change nephrosis, focal segmental glomerulosclerosis, and membranous nephropathy, the distribution of nephrin was similar to that in controls. In proliferative forms of glomerulonephritides (Henoch-Schönlein nephritis, IgA nephropathy, postinfectious and membranoproliferative glomerulonephritis), crescents and sclerotic lesions were negative for nephrin, and mesangial proliferation led to a scattered and sparse staining pattern. The staining pattern of nephrin was compared to that of ZO-1, a component of the cytoplasmic face of the slit diaphragm. The distributions of these two proteins in capillary tufts were similar in all disease entities studied. In conclusion, immunohistochemistry andin situhybridization did not reveal major alterations in the expression of nephrin in proteinuric kidney diseases in children. Further studies are needed for more precise evaluation of the role of nephrin in these diseases.

Pathogenesis of proteinuria in minimal change disease and focal segmental glomerulosclerosis

2018 ◽  
Author(s):  
Patrick Niaudet ◽  
Alain Meyrier
Keyword(s):  
Serum Albumin ◽  
Focal Segmental Glomerulosclerosis ◽  
Minimal Change Disease ◽  
Minimal Change ◽  
Slit Diaphragm ◽  
Segmental Glomerulosclerosis ◽  
Podocyte Loss ◽  
Glomerular Filtrate

It is now well established that the podocyte, and in particular the slit diaphragm structure, are critical to the barrier to serum albumin entering glomerular filtrate in large quantities. In minimal change disease there is proteinuria without podocyte death, whereas in focal segmental glomerulosclerosis there is not only podocyte dysfunction but also podocyte loss.

scholarly journals The transcriptional regulation of Podocin (NPHS2) by Lmx1b and a promoter single nucleotide polymorphism

2009 ◽  
Vol 14 (4) ◽  
Author(s):  
Sigrid Harendza ◽  
Rolf Stahl ◽  
André Schneider
Keyword(s):  
Transcription Factor ◽  
Transcriptional Regulation ◽  
Nephrotic Syndrome ◽  
Focal Segmental Glomerulosclerosis ◽  
Membranous Nephropathy ◽  
Minimal Change ◽  
Renal Diseases ◽  
Single Nucleotide ◽  
Segmental Glomerulosclerosis ◽  
Minimal Change Glomerulonephritis

AbstractPodocin (NPHS2) is a component of the glomerular slit membrane with major regulatory functions in the renal permeability of proteins. A loss of podocin and a decrease in its resynthesis can influence the outcome of renal diseases with nephrotic syndrome, such as minimal change glomerulonephritis, focal segmental glomerulosclerosis (FSGS) and membranous nephropathy. The transcriptional regulation of podocin may play a major role in these processes. We defined the transcriptional regulation of the human podocin gene and the influence of single nucleotide polymorphisms (SNPs) within its promoter region in the podocytes using reporter gene constructs and gel shift analysis. In addition, we took genomic DNA from healthy Caucasian blood donors and from biopsies of kidneys with defined renal diseases and screened it for podocin promoter SNPs. Our data shows that the transcription of podocin is mainly regulated by the transcription factor Lmx1b, which binds to a FLAT-F element and displays enhancer function. With the SNP variant −116T, there was a significant reduction in luciferase activity, and nuclear protein binding was observed, while the SNP −670C/T did not display functionality. The allelic distribution of −116C/T in patients with kidney diseases leading to nephrotic syndrome was not significantly different from that in the control group. Our data indicates that among other factors, podocin is specifically regulated by the transcription factor Lmx1b and by the functional polymorphism -116C/T. However, there is no association between −116C/T and susceptibility to minimal change glomerulonephritis, focal segmental glomerulosclerosis or membranous nephropathy.

scholarly journals Loss of phosphatidylserine flippase β-subunit Tmem30a in podocytes leads to albuminuria and glomerulosclerosis

2020 ◽  
Author(s):  
Wenjing Liu ◽  
Lei Peng ◽  
Wanli Tian ◽  
Yi Li ◽  
Ping Zhang ◽  
...  
Keyword(s):  
Focal Segmental Glomerulosclerosis ◽  
Membranous Nephropathy ◽  
Minimal Change Disease ◽  
Critical Role ◽  
Minimal Change ◽  
Mouse Retina ◽  
Β Subunit ◽  
Filtration Barrier ◽  
Segmental Glomerulosclerosis

AbstractPhosphatidylserine (PS) is asymmetrically concentrated in the cytoplasmic leaflet of eukaryotic cell plasma membranes. This asymmetry is regulated by a group of P4 ATPases (named PS flippases) and its β-subunit TMEM30A. The disruption of PS flippase leads to severe human diseases. Tmem30a is essential in the mouse retina, cerebellum and liver. However, the role of Tmem30a in the kidney, where it is highly expressed, remains unclear. Podocytes in the glomerulus form a branched interdigitating filtration barrier that can prevent the traversing of large cellular elements and macromolecules from the blood into the urinary space. Damage to podocytes can disrupt the filtration barrier and lead to proteinuria and podocytopathy, including focal segmental glomerulosclerosis, minimal change disease, membranous nephropathy, and diabetic nephropathy. To investigate the role of Tmem30a in the kidney, we generated a podocyte-specific Tmem30a knockout (cKO) mouse model using the NPHS2-Cre line. Tmem30a KO mice displayed albuminuria, podocyte degeneration, mesangial cell proliferation with prominent extracellular matrix accumulation and eventual progression to focal segmental glomerulosclerosis (FSGS). Reduced TMEM30A expression was observed in patients with minimal change disease and membranous nephropathy, highlighting the clinical importance of TMEM30A in podocytopathy. Our data demonstrate a critical role of Tmem30a in maintaining podocyte survival and glomerular filtration barrier integrity. Understanding the dynamic regulation of the PS distribution in the glomerulus provides a unique perspective to pinpoint the mechanism of podocyte damage and potential therapeutic targets.

scholarly journals Loss of phosphatidylserine flippase β-subunit Tmem30a in podocytes leads to albuminuria and glomerulosclerosis

2021 ◽  
Author(s):  
Wenjing Liu ◽  
Lei Peng ◽  
Wanli Tian ◽  
Yi Li ◽  
Ping Zhang ◽  
...  
Keyword(s):  
Focal Segmental Glomerulosclerosis ◽  
Membranous Nephropathy ◽  
Minimal Change Disease ◽  
Critical Role ◽  
Minimal Change ◽  
Mouse Retina ◽  
Β Subunit ◽  
Filtration Barrier ◽  
Segmental Glomerulosclerosis

Phosphatidylserine (PS) is asymmetrically concentrated in the cytoplasmic leaflet of eukaryotic cell plasma membranes. This asymmetry is regulated by a group of P4 ATPases (named PS flippases) and its β-subunit TMEM30A. The disruption of PS flippase leads to severe human diseases. Tmem30a is essential in the mouse retina, cerebellum and liver. However, the role of Tmem30a in the kidney, where it is highly expressed, remains unclear. Podocytes in the glomerulus form a branched interdigitating filtration barrier that can prevent the traversing of large cellular elements and macromolecules from the blood into the urinary space. Damage to podocytes can disrupt the filtration barrier and lead to proteinuria and podocytopathy, including focal segmental glomerulosclerosis, minimal change disease, membranous nephropathy, and diabetic nephropathy. We observed reduced TMEM30A expression in patients with minimal change disease and membranous nephropathy, indicating potential roles of TMEM30A in podocytopathy. To investigate the role of Tmem30a in the kidney, we generated a podocyte-specific Tmem30a knockout (KO) mouse model using the NPHS2-Cre line. Tmem30a KO mice displayed albuminuria, podocyte degeneration, mesangial cell proliferation with prominent extracellular matrix accumulation and eventual progression to focal segmental glomerulosclerosis (FSGS). Our data demonstrate a critical role of Tmem30a in maintaining podocyte survival and glomerular filtration barrier integrity. Understanding the dynamic regulation of the PS distribution in the glomerulus provides a unique perspective to pinpoint the mechanism of podocyte damage and potential therapeutic targets.

scholarly journals Kidney Injury by Variants in the COL4A5 Gene Aggravated by Polymorphisms in Slit Diaphragm Genes Causes Focal Segmental Glomerulosclerosis

2019 ◽  
Vol 20 (3) ◽  
pp. 519 ◽  
Author(s):  
Jenny Frese ◽  
Matthias Kettwig ◽  
Hildegard Zappel ◽  
Johannes Hofer ◽  
Hermann-Josef Gröne ◽  
...  
Keyword(s):  
Renal Failure ◽  
Basement Membrane ◽  
Focal Segmental Glomerulosclerosis ◽  
Glomerular Basement Membrane ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Slit Diaphragm ◽  
Filtration Barrier ◽  
Segmental Glomerulosclerosis ◽  
Case Series Study

Kidney injury due to focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular disorder causing end-stage renal disease. Homozygous mutations in either glomerular basement membrane or slit diaphragm genes cause early renal failure. Heterozygous carriers develop renal symptoms late, if at all. In contrast to mutations in slit diaphragm genes, hetero- or hemizygous mutations in the X-chromosomal COL4A5 Alport gene have not yet been recognized as a major cause of kidney injury by FSGS. We identified cases of FSGS that were unexpectedly diagnosed: In addition to mutations in the X-chromosomal COL4A5 type IV collagen gene, nephrin and podocin polymorphisms aggravated kidney damage, leading to FSGS with ruptures of the basement membrane in a toddler and early renal failure in heterozygous girls. The results of our case series study suggest a synergistic role for genes encoding basement membrane and slit diaphragm proteins as a cause of kidney injury due to FSGS. Our results demonstrate that the molecular genetics of different players in the glomerular filtration barrier can be used to evaluate causes of kidney injury. Given the high frequency of X-chromosomal carriers of Alport genes, the analysis of genes involved in the organization of podocyte architecture, the glomerular basement membrane, and the slit diaphragm will further improve our understanding of the pathogenesis of FSGS and guide prognosis of and therapy for hereditary glomerular kidney diseases.

scholarly journals Application of geostatistical functions and deep features to kidney biopsy images to differentiate focal segmental glomerulosclerosis from minimal change disease

2020 ◽  
Author(s):  
Justino Duarte Santos ◽  
Romuere R. V. Silva ◽  
Rodrigo M. S. Veras
Keyword(s):  
Focal Segmental Glomerulosclerosis ◽  
Minimal Change Disease ◽  
Kidney Diseases ◽  
Image Features ◽  
Information Criteria ◽  
Minimal Change ◽  
Kappa Index ◽  
Accurate Identification ◽  
Chronic Kidney Diseases ◽  
Segmental Glomerulosclerosis

Chronic kidney diseases arise from acute or intermittent pathologies that have not been adequately treated, such as minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). The accurate identification of these two diseases is of paramount importance, because their treatments and prognoses are different. Thus, we propose a method that is capable of differentiating MCD from FSGS based on images from pathological examinations. In the proposed method, we use four pre-trained convolutional neural networks and geostatistical functions to extract image features. Of the 8,720 extracted features, we selected 94 based on mutual information criteria, and in the classification step, we used a random forest classifier. The proposed method obtained an accuracy of 94.3% and Kappa index of 87.9%, a level that is regarded as “almost perfect”, confirming that our method is very promising.

scholarly journals In situ evaluation of podocytes in patients with focal segmental glomerulosclerosis and minimal change disease

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0241745
Author(s):  
Crislaine Aparecida da Silva ◽  
Maria Luíza Gonçalves dos Reis Monteiro ◽  
Liliane Silvano Araújo ◽  
Monise Gini Urzedo ◽  
Lenaldo Branco Rocha ◽  
...  
Keyword(s):  
Focal Segmental Glomerulosclerosis ◽  
Minimal Change Disease ◽  
Minimal Change ◽  
Segmental Glomerulosclerosis

scholarly journals Rituximab Therapy for Adults with Nephrotic Syndromes: Standard Schedules or B Cell-Targeted Therapy?

2021 ◽  
Vol 10 (24) ◽  
pp. 5847
Author(s):  
Lucia Del Vecchio ◽  
Marco Allinovi ◽  
Paolo Rocco ◽  
Bruno Brando
Keyword(s):  
B Cells ◽  
B Cell ◽  
Focal Segmental Glomerulosclerosis ◽  
Membranous Nephropathy ◽  
Minimal Change Disease ◽  
Minimal Change ◽  
Segmental Glomerulosclerosis ◽  
Steroid Dependent ◽  
B Cell Subsets ◽  
Anti Cd20

Rituximab is a chimeric anti-CD20 monoclonal antibody. It acts mainly through complement-dependent cytotoxicity on B cells expressing the CD20 marker. In this review, we analyse the efficacy and possible pitfalls of rituximab to treat nephrotic syndromes by taking into account pharmacological considerations and CD19 marker testing utility. Despite the fact that the drug has been in use for years, efficacy and treatment schedules in adults with nephrotic syndrome are still a matter of debate. Clinical trials have proven the efficacy and safety of rituximab in idiopathic membranous nephropathy. Data from observational studies also showed the efficacy of rituximab in minimal change disease and focal segmental glomerulosclerosis. Rituximab use is now widely recommended by new Kidney Disease Improved Outcome (KDIGO) guidelines in membranous nephropathy and in frequent-relapsing, steroid-dependent minimal change disease or focal segmental glomerulosclerosis. However, rituximab response has a large interindividual variability. One reason could be that rituximab is lost in the urine at a higher extent in patients with nonselective nephrotic proteinuria, exposing patients to different rituximab plasma levels. Moreover, the association between CD19+ levels and clinical response or relapses is not always present, making the use of this marker in clinical practice complex. High resolution flow cytometry has increased the capability of detecting residual CD19+ B cells. Moreover, it can identify specific B-cell subsets (including IgG-switched memory B cells), which can repopulate at different rates. Its wider use could become a useful tool for better understanding reasons of rituximab failure or avoiding unnecessary retreatments.

scholarly journals Glomerular Expression of Dystroglycans Is Reduced in Minimal Change Nephrosis But Not in Focal Segmental Glomerulosclerosis

2000 ◽  
Vol 11 (3) ◽  
pp. 403-412 ◽  
Author(s):  
HEINRICH M. REGELE ◽  
EDITH FILLIPOVIC ◽  
BRIGITTE LANGER ◽  
HELGA POCZEWKI ◽  
ILSE KRAXBERGER ◽  
...  
Keyword(s):  
Focal Segmental Glomerulosclerosis ◽  
Immunoelectron Microscopy ◽  
Minimal Change ◽  
Matrix Proteins ◽  
Membrane Domains ◽  
Segmental Glomerulosclerosis ◽  
Pathologic Features ◽  
Minimal Change Nephrosis ◽  
Foot Process ◽  
Quantitative Immunoelectron Microscopy

Abstract. Extensive flattening of podocyte foot processes and increased permeability of the glomerular capillary filter are the major pathologic features of minimal change nephrosis (MCN) and focal segmental glomerulosclerosis (FSGS). Adhesion proteins anchor and stabilize podocytes on the glomerular basement membrane (GBM), and presumably are involved in the pathogenesis of foot process flattening. Thus far, α3 β1-integrin was localized to basal cell membrane domains. In this report, α- and β-dystroglycan (DG) were detected at precisely the same location by immunoelectron microscopy, and the presence of α- and β-DG chains was confirmed by immunoblotting on isolated human glomeruli. Because the major DG binding partners in the GBM (laminin, agrin, perlecan), and the intracellular dystrophin analogue utrophin are also present in glomeruli, it appears that podocytes adhere to the GBM via DG complexes, similar to muscle fibers in which actin is linked via dystrophin and DG to the extracellular matrix. As with muscle cells, it is therefore plausible that podocytes use precisely actin-guided DG complexes at their “soles” to actively govern the topography of GBM matrix proteins. Expression of the α/β-DG complex was reported to be reduced in muscular dystrophies, and therefore a search for similar pathologic alterations in archival kidney biopsies from patients with MCN (n = 16) and FSGS (n = 8) was conducted by quantitative immunoelectron microscopy. The density of α-DG on the podocyte's soles was significantly reduced to 25% in MCN, whereas it was not different in normal kidneys and FSGS. The expression of β-DG was reduced to >50% in MCN, and was slightly increased in FSGS. Levels of DG expression returned to normal in MCN after steroid treatment (n = 4). Expression of β1-integrin remained at normal levels in all conditions. These findings point to different potentially pathogenic mechanisms of foot process flattening in MCN and FSGS.

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