Dissociation of NEPH1 from nephrin is involved in development of a rat model of focal segmental glomerulosclerosis

2008 ◽  
Vol 295 (5) ◽  
pp. F1376-F1387 ◽  
Author(s):  
Yasuhiro Otaki ◽  
Naoko Miyauchi ◽  
Mutsumi Higa ◽  
Akira Takada ◽  
Takeshi Kuroda ◽  
...  
Keyword(s):  
Focal Segmental Glomerulosclerosis ◽  
Rat Model ◽  
Critical Role ◽  
Glomerular Capillary Wall ◽  
Morphological Alterations ◽  
Initiation Phase ◽  
Segmental Glomerulosclerosis ◽  
Glomerular Epithelial Cells ◽  
End Stage

Focal segmental glomerulosclerosis (FSGS) is a disease showing severe proteinuria, and the disease progresses to end-stage kidney failure in many cases. However, the pathogenic mechanism of FSGS is not well understood. The slit diaphragm (SD), which bridges the neighboring foot processes of glomerular epithelial cells, is understood to function as a barrier of the glomerular capillary wall. To investigate the role of SD dysfunction in the development of FSGS, we analyzed the expression of SD-associated molecules in rat adriamycin-induced nephropathy, a mimic of FSGS. The staining of the SD molecules nephrin, podocin, and NEPH1 had already shifted to a discontinuous dotlike pattern at the initiation phase of the disease, when neither proteinuria nor any morphological alterations were detected yet. The alteration of NEPH1 expression was the most evident among the molecules examined, and NEPH1 was dissociated from nephrin at the initiation phase. On day 28, when severe proteinuria was detected and sclerotic changes were already observed, alteration of the expressions of nephrin, podocin, and NEPH1 worsened, but no alteration in the expression of other SD-associated molecules or other podocyte molecules was detected. It is postulated that the dissociation of NEPH1 from nephrin initiates proteinuria and that the SD alteration restricted in these molecules plays a critical role in the development of sclerotic changes in FSGS.

Role of autophagy and evaluation the effects of microRNAs 214, 312, 34c and prorenin receptor in a rat model of focal segmental glomerulosclerosis

Life Sciences ◽  
2021 ◽  
pp. 119671
Author(s):  
Derya Yildirim ◽  
Onur Bender ◽  
Zehra Firat Karagoz ◽  
Fatma Helvacioglu ◽  
Mukadder Ayse Bilgic ◽  
...  
Keyword(s):  
Focal Segmental Glomerulosclerosis ◽  
Rat Model ◽  
Segmental Glomerulosclerosis ◽  
Prorenin Receptor

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 Potential role of Claudin-1 immunohistochemical expression and ultrastructural changes in detecting early focal segmental glomerulosclerosis

2019 ◽  
Vol 8 (3) ◽  
pp. 24-24
Author(s):  
Nadia Galal Elhefnawy ◽  
Nermine Mohamed Adb Raboh ◽  
Ola Hassan Nada ◽  
Esraa Adel Mahmoud ◽  
Waleed Anwar Abd El Mohsen
Keyword(s):  
Nephrotic Syndrome ◽  
Focal Segmental Glomerulosclerosis ◽  
Ultrastructural Changes ◽  
Segmental Glomerulosclerosis ◽  
Disease Entities ◽  
Sclerotic Lesions ◽  
Stage Renal Disease ◽  
End Stage ◽  
Parietal Epithelial Cells

Background: Focal segmental glomerulosclerosis (FSGS) and Minimal change disease (MCD) are two disease entities presented mainly by nephrotic syndrome. While 95% of MCD cases showed complete remission on steroid therapy, 50% of FSGS cases progress to end stage renal disease. Early sclerotic lesions in FSGS can be missed in routine H&E examination. Objective: To differentiate early FSGS from MCD by detection of activated parietal epithelial cells (PECs) in early glomerular sclerotic lesions using Claudin-1 immunohistochemical (IHC) staining and by examining podocyte ultrastructural changes. Materials and Methods: This retrospective study included 28 cases diagnosed as MCD and 20 cases diagnosed as early FSGS. Clinicopathologic data collection, claudin-1 IHC staining and reviewing ultrastructural changes were performed and the results were statistically analyzed. Results: A statistically significant correlation was detected between claudin-1 expression and the initial diagnosis of the studied groups (P=0.005). Claudin-1 was expressed in a visceral location in (39.28%) of the biopsies initially diagnosed as MCD thus were reevaluated as early FSGS lesions. 63.64% of these positive cases were presented by steroid resistant nephrotic syndrome and 63.6% of which showed some ultrastructural changes of FSGS in podocytes including abnormalities in mitochondrial shapes, endoplasmic reticulum changes and a decreased number of autophagic vacuoles. Conclusion: Claudin-1 is a novel diagnostic marker that can differentiate between confusing cases of early FSGS versus MCD. Defective autophagy plays a role in the pathogenesis of FSGS.

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 Morphological Alterations and Increased S100B Expression in Epidermal Langerhans Cells Detected in Skin from Patients with Progressive Vitiligo

Life ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 579
Author(s):  
Fei Yang ◽  
Lingli Yang ◽  
Lanting Teng ◽  
Huimin Zhang ◽  
Ichiro Katayama
Keyword(s):  
Electron Microscopy ◽  
Langerhans Cells ◽  
Critical Role ◽  
Light And Electron Microscopy ◽  
Morphological Alterations ◽  
Birbeck Granules ◽  
Immuno Electron Microscopy ◽  
Skin Biopsies ◽  
Epidermal Langerhans Cells

The role of Langerhans cells (LCs) in vitiligo pathogenesis remains unclear, with published studies reporting contradictory results regarding the quantity of LCs and no data on the features of LCs in vitiligo. Here, we aimed to analyze the presence, density, and morphological features of LCs in the epidermis of patients with vitiligo. Skin biopsies were stained for LCs using anti-CD1a/anti-langerin antibodies and analyzed by immunocytochemistry with light and electron microscopy. Compared with healthy controls, we detected significantly increased numbers of epidermal LCs in lesional skin from vitiligo in the progressive state. These LCs exhibited striking morphological alterations, including an elevated number of dendrites, with increased length and more branches than dendrites from controls. Ultrastructure examination via immuno-electron microscopy revealed markedly reduced Birbeck granules (BGs) and shorter BG rods in LCs from progressive vitiligo, with higher expression of langerin. Additionally, expression of S100B, the activity biomarker of vitiligo, was increased in these LCs. This work provides new insight on the cellular composition of LCs in vitiliginous skin, revealing altered morphology and increased LC numbers, with elevated S100B expression. Our data suggest LCs might play a critical role in vitiligo pathogenesis and thus may represent a novel therapeutic target for this disease.

scholarly journals Moxibustion Alleviates Injury in a Rat Focal Segmental Glomerulosclerosis Model

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Yi Li ◽  
Yuxia Sun ◽  
Chunling Zhang ◽  
Ke Wang ◽  
Peicheng Shen ◽  
...  
Keyword(s):  
Focal Segmental Glomerulosclerosis ◽  
Rat Model ◽  
Interstitial Fibrosis ◽  
Similar Efficacy ◽  
Glomerular Sclerosis ◽  
Control Group ◽  
Therapeutic Effects ◽  
Repeated Injection ◽  
Moxibustion Group ◽  
Segmental Glomerulosclerosis

Objectives. To evaluate the therapeutic effects of moxibustion at Shenshu (BL-23) and Geshu (BL-17) acupoints in a focal segmental glomerulosclerosis (FSGS) model in rats. Methods. A FSGS rat model was established by single nephrectomy and repeated injection of doxorubicin. The FSGS rats were randomly divided into the model group, losartan (positive control) group, Shenshu moxibustion group, and Geshu moxibustion group. Molecular indicators of kidney function and renal pathological changes were monitored. Results. Urinary protein, serum creatinine, urea nitrogen, and serum uric acid were significantly reduced after 12-week intervention with losartan, Shenshu, or Geshu moxibustion. Renal α-SMA, FN, and TGF-β were also decreased, while podocin and nephrin protein and mRNA were increased. The pathological damage in renal tissue was obviously alleviated by all three treatments, which suggests that moxibustion may have similar efficacy to losartan in the treatment of FSGS. Conclusion. Moxibustion alleviates podocyte injury and inhibits renal interstitial fibrosis in the FSGS rat model, thereby minimizing the progression of glomerular sclerosis and improving renal function.

scholarly journals PROTEINURIA IN FOCAL SEGMENTAL GLOMERULOSCLEROSIS: ROLE OF CIRCULATING FACTORS AND THERAPEUTIC APPROACH

Renal Failure ◽  
2001 ◽  
Vol 23 (3-4) ◽  
pp. 533-541 ◽  
Author(s):  
Luigi Moriconi ◽  
Ciro Lenti ◽  
Rodolfo Puccini ◽  
Antonio Pasquariello ◽  
Paolo Rindi ◽  
...  
Keyword(s):  
Focal Segmental Glomerulosclerosis ◽  
Therapeutic Approach ◽  
Segmental Glomerulosclerosis

scholarly journals Clinical and laboratory features that differentiate familial from sporadic focal segmental glomerulosclerosis in adolescents and adults

2021 ◽  
Vol 6 (1) ◽  
pp. 1-5
Author(s):  
Maria Goretti Polito ◽  
Michelle Tiveron Passos ◽  
Danilo Euclides Fernandes ◽  
Gianna Mastroianni-Kirsztajn
Keyword(s):  
Serum Albumin ◽  
Focal Segmental Glomerulosclerosis ◽  
Steroid Resistance ◽  
End Stage Kidney Disease ◽  
Steroid Resistant ◽  
Best Management ◽  
Segmental Glomerulosclerosis ◽  
Laboratory Features ◽  
Adolescents And Adults ◽  
End Stage

Background: Focal segmental glomerulosclerosis (FSGS) is an important cause of end-stage kidney disease in children and adults. Although most cases are sporadic (s), familial (f) presentation is also described. The purpose of the present study was to establish clinical and laboratory profiles of fFSGS vs. primary sFSGS, contributing to the distinguishing diagnosis in clinical practice and best management, in particular when mutation analysis is not available. Methods: Demographic, clinical and laboratorial parameters were studied in 124 patients 12 years and older with FSGS, subdivided in sFSGS (n=89) and fFSGS (n=35). Results: General and clinical features were similar, as well as serum creatinine at disease presentation. Proteinuria levels were more frequently ≥ 3g/day in sFSGS (63.8%) than in fFSGS (44%, p=0.080), and serum albumin levels were < 3.0 g/dL in 45.8% and 20%, respectively (p=0.046). The groups were statistically different regarding steroid resistance, corresponding to 60% in sFSGS and 100% in fFSGS (p=0.001). Conclusions: The studied groups were clinically similar, except that proteinuria tended to be higher (nephrotic range) and serum albumin was lower in sFSGS vs. fFSGS. In addition, all treated fFSGS patients were steroid resistant. At presentation it is important to characterize if the patient has fFSGS, that will contribute to further disease management, and disease history will be the first clue for such differential diagnosis.

scholarly journals Inherited podocytopathies

2008 ◽  
Vol 136 (Suppl. 4) ◽  
pp. 327-339
Author(s):  
Radovan Bogdanovic
Keyword(s):  
Congenital Nephrotic Syndrome ◽  
Structural Studies ◽  
Glomerular Filtration Barrier ◽  
Filtration Barrier ◽  
Glomerular Epithelial Cells ◽  
Causes Of Disease ◽  
Stage Renal Disease ◽  
End Stage ◽  
Made In

Podocytes, the visceral glomerular epithelial cells, are the postmythotic cells that line the outer aspects of the glomerular basement membrane. A number of advances have been made in recent years, linked to the discovery of singlegene defects in hereditary glomerular disease, which highlight the role of these cells in preventing proteinuria. Despite the rarity of hereditary proteinuric syndromes, genetic, biochemical, and structural studies of these diseases have made important contributions to our knowledge of how the normal glomerular filter works and the mechanism of proteinuria. The course of these diseases can vary; some patients present with severe proteinuria and congenital nephrotic syndrome, whereas others have only moderate proteinuria and focal segmental glomerulosclerosis. Regardless of its cause, the disease often progresses to end-stage renal disease. There can be overlap between the diseases: mutations in the same gene can lead to different renal phenotypes. It is important to know that some hereditary podocytopathies respond to therapy, whereas majority does not. For this reason, genetic testing, which is available for some hereditary podocytopathies should be performed whenever possible. This review summarizes recent progress in the eludication of genetic causes of disease and discusses their implication for the understanding of the pathogenic mechanisms which can lead to disruption of the glomerular filtration barrier.

scholarly journals Focal Segmental Glomerulosclerosis

1999 ◽  
Vol 10 (9) ◽  
pp. 1900-1907
Author(s):  
MELVIN M. SCHWARTZ ◽  
JONI EVANS ◽  
RAY BAIN ◽  
STEPHEN M. KORBET
Keyword(s):  
Serum Creatinine ◽  
Focal Segmental Glomerulosclerosis ◽  
End Stage Renal Disease ◽  
Poor Response ◽  
Steroid Treatment ◽  
Response To Treatment ◽  
Therapeutic Trial ◽  
Segmental Glomerulosclerosis ◽  
Stage Renal Disease ◽  
End Stage

Abstract. The cellular lesion (CELL), seen in some patients with primary focal segmental glomerulosclerosis (FSGS), comprises proliferation, hypertrophy, and pathologic changes in the cells overlying the glomerular scar. The prognosis of the cellular lesion was retrospectively studied in 100 patients with FSGS (43 had FSGS-CELL and 57 had FSGS without the cellular lesion (classic segmental scar [CS]). Patients with the FSGS-CELL lesion were more often black and severely proteinuric and developed more end-stage renal disease (ESRD). Nephrotic patients with FSGS-CELL (n = 39) were more proteinuric at presentation than patients with FSGS-CS (n = 36). ESRD developed more frequently in patients with the FSGS-CELL (17 of 39, 44% versus 5 of 36, 14%, P = 0.005), and patients with extensive FSGS-CELL (≥ 20% glomeruli) were mainly black (94%), severely nephrotic (67%, >10 g/d), and had a poor response to treatment (23% remission). In nephrotic patients, initial serum creatinine, interstitial expansion ≥20%, and CELL independently predicted ESRD. However, the rates of remission in treated nephrotic patients with FSGS-CELL and FSGS-CS were the same (9 of 17, 53% versus 17 of 39, 52%), and patients in both groups who achieved a remission had a 5-yr survival of 100%. Steroid treatment was the only variable that predicted remission. Patients with the FSGS-CELL have an increased prevalence of ESRD, but the improved prognosis associated with remission is so significant that a therapeutic trial is warranted in all nephrotic FSGS patients, regardless of the presence of the cellular lesion.

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