scholarly journals Reversible glomerular hypertrophy in adult patients with primary focal segmental glomerulosclerosis.

1997 ◽  
Vol 8 (11) ◽  
pp. 1668-1678
Author(s):  
K Nishimoto ◽  
H Shiiki ◽  
T Nishino ◽  
H Uyama ◽  
M Iwano ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Focal Segmental Glomerulosclerosis ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Cell Number ◽  
Glomerular Hypertrophy ◽  
Control Subjects ◽  
Segmental Glomerulosclerosis ◽  
The Mean ◽  
Glomerular Tuft

The present study was performed to assess the pathogenetic role of glomerular hypertrophy in patients with primary focal segmental glomerulosclerosis (FSGS). We studied 14 patients with FSGS by morphometry. In seven patients, minimal change nephrotic syndrome (MCNS) was diagnosed on the first renal biopsy, but FSGS was diagnosed on the second biopsy (MCNS-FSGS group). Seven other patients with FSGS on the first biopsy underwent second biopsies while in remission (FSGS-R group). Biopsy results were compared with biopsies from 10 patients with MCNS and seven control subjects. Nonsclerotic glomeruli were examined. The mean glomerular tuft area, whole glomerular area, and number of mesangial cells were significantly increased in both biopsies from the MCNS-FSGS group and in the first biopsies obtained during the nephrotic stage of the FSGS-R group, compared with control subjects and patients with MCNS. Biopsies from FSGS patients in remission showed that the mean glomerular tuft area and number of mesangial cells were significantly decreased. The fractional extracellular matrix area (extracellular matrix area/glomerular tuft area) and mesangial cell density (mesangial cell number/glomerular tuft area) in FSGS during both nephrotic and remission stages were the same as those in control subjects and patients with MCNS. The present study suggests that glomerular hypertrophy precedes the development of glomerulosclerosis in FSGS and is reversible when patients are in remission. These features support the pathogenetic importance of glomerular hypertrophy in patients with primary FSGS.

scholarly journals Kidney glycosphingolipids are elevated early in diabetic nephropathy and mediate hypertrophy of mesangial cells

2015 ◽  
Vol 309 (3) ◽  
pp. F204-F215 ◽  
Author(s):  
Marimuthu Subathra ◽  
Midhun Korrapati ◽  
Lauren A. Howell ◽  
John M. Arthur ◽  
James A. Shayman ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Diabetic Nephropathy ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Extracellular Matrix Proteins ◽  
Matrix Proteins ◽  
Limited Attention ◽  
Glomerular Hypertrophy ◽  
Glucosylceramide Synthase ◽  
Cell Hypertrophy

Glycosphingolipids (GSLs) play a role in insulin resistance and diabetes, but their role in diabetic nephropathy (DN) has received limited attention. We used 9- and 17-wk-old nondiabetic db/ m and diabetic db/ db mice to examine the role of GSLs in DN. Cerebrosides or monoglycosylated GSLs [hexosylceramides (HexCers); glucosyl- and galactosylceramides] and lactosylceramide (LacCers) were elevated in db/ db mouse kidney cortices, specifically in glomeruli, and also in urine. In our recent paper (25), we observed that the kidneys exhibited glomerular hypertrophy and proximal tubular vacuolization and increased fibrosis markers at these time points. Mesangial cells contribute to hyperglycemia-induced glomerular hypertrophy in DN. Hyperglycemic culture conditions, similar to that present in diabetes, were sufficient to elevate mesangial cell HexCers and increase markers of fibrosis, extracellular matrix proteins, and cellular hypertrophy. Inhibition of glucosylceramide synthase or lowering glucose levels decreased markers of fibrosis and extracellular matrix proteins and reversed mesangial cell hypertrophy. Hyperglycemia increased phosphorylated (p)SMAD3 and pAkt levels and reduced phosphatase and tensin homolog levels, which were reversed with glucosylceramide synthase inhibition. These data suggest that inhibition of glucosylceramide synthase reversed mesangial cell hypertrophy through decreased pAkt and pSmad3 and increased pathways responsible for protein degradation. Importantly, urinary GSL levels were higher in patients with DN compared with healthy control subjects, implicating a role for these lipids in human DN. Thus, hyperglycemia in type II diabetes leads to renal dysfunction at least in part by inducing accumulation of HexCers and LacCers in mesangial cells, resulting in fibrosis, extracellular matrix production, and hypertrophy.

Hypoxia and high glucose cause exaggerated mesangial cell growth and collagen synthesis: role of osteopontin

2001 ◽  
Vol 280 (4) ◽  
pp. F667-F674 ◽  
Author(s):  
Chhinder P. Sodhi ◽  
Sarojini A. Phadke ◽  
Daniel Batlle ◽  
Atul Sahai
Keyword(s):  
Cell Growth ◽  
High Glucose ◽  
Collagen Synthesis ◽  
Type Iv Collagen ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Neutralizing Antibody ◽  
Cell Number ◽  
Mrna Levels ◽  
Type Iv

The effect of hypoxia on the proliferation and collagen synthesis of cultured rat mesangial cells was examined under normal-glucose (NG, 5 mM) and high-glucose (HG, 25 mM)-media conditions. In addition, a role for osteopontin (OPN) in mediating these processes was assessed. Quiescent cultures were exposed to hypoxia (3% O2) and normoxia (18% O2) in a serum-free medium with NG or HG, and cell proliferation, collagen synthesis, and OPN expression were assessed. Cells exposed to hypoxia in NG medium resulted in significant increases in [3H]thymidine incorporation, cell number, and [3H]proline incorporation, respectively. HG incubations also produced significant stimulation of these parameters under normoxic conditions, which were markedly enhanced in cells exposed to hypoxia in HG medium. In addition, hypoxia and HG stimulated the mRNA levels of type IV collagen, and the combination of hypoxia and HG resulted in additive increases in type IV collagen expression. Hypoxia and HG also stimulated OPN mRNA and protein levels in an additive fashion. A neutralizing antibody to OPN or its β3-integrin receptor significantly blocked the effect of hypoxia and HG on proliferation and collagen synthesis. In conclusion, these results demonstrate for the first time that hypoxia in HG medium produces exaggerated mesangial cell growth and type IV collagen synthesis. In addition, OPN appears to play a role in mediating the accelerated mesangial cell growth and collagen synthesis found in a hyperglycemic and hypoxic environment.

scholarly journals LncRNA NEAT1 Promotes High Glucose-Induced Mesangial Cell Hypertrophy by Targeting miR-222-3p/CDKN1B Axis

2021 ◽  
Vol 7 ◽  
Author(s):  
Lin Liao ◽  
Jie Chen ◽  
Chuanfu Zhang ◽  
Yue Guo ◽  
Weiwei Liu ◽  
...  
Keyword(s):  
High Glucose ◽  
Noncoding Rna ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Morphological Alteration ◽  
Glomerular Hypertrophy ◽  
Cell Hypertrophy ◽  
Rna Immunoprecipitation ◽  
Lncrna Neat1

Glomerular hypertrophy is an early morphological alteration in diabetic nephropathy. Cyclin-Dependent Kinases have been shown to be required for high glucose (HG)-induced hypertrophy; however, the upstream regulators of CDKN1B in glomerular hypertrophy remain unclear. Herein we describe a novel pathway in which Long noncoding RNA (lncRNA) NEAT1 regulates the progression of mesangial cell hypertrophy via a competing endogenous RNA (ceRNA) mechanism. Real-time PCR was performed to detect the relative NEAT1 and miR-222-3p expressions and further confirmed the relationship between NEAT1 and miR-222-3p. Cell cycle was evaluated by flow cytometry. The related mechanisms were explored by Western blot, RNA immunoprecipitation and chromatin immunoprecipitation assay. We show that NEAT1 forms double stranded RNA (dsRNA) with miR-222-3p, thus limiting miR-222-3p’s binding with CDKN1B. This release of CDKN1B mRNA leads to elevated CDKN1B protein expression, resulting in hypertrophy. In addition, we demonstrated that STAT3 which is activated by HG induces the transcription of NEAT1 by binding to its promoter. Our findings underscore an unexpected role of lncRNAs on gene regulation and introduce a new mode of proliferation regulation in mesangial cells.

scholarly journals Differential expression of parietal epithelial cell and podocyte extracellular matrix proteins in focal segmental glomerulosclerosis and diabetic nephropathy

2019 ◽  
Vol 317 (6) ◽  
pp. F1680-F1694 ◽  
Author(s):  
Gek Cher Chan ◽  
Diana G. Eng ◽  
Jeffrey H. Miner ◽  
Charles E. Alpers ◽  
Kelly Hudkins ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Diabetic Nephropathy ◽  
Epithelial Cell ◽  
Focal Segmental Glomerulosclerosis ◽  
Collagen Type ◽  
Collagen Type Iv ◽  
Type Iv ◽  
Ecm Proteins ◽  
Segmental Glomerulosclerosis ◽  
Parietal Epithelial Cell

In healthy glomeruli, parietal epithelial cell (PEC)-derived extracellular matrix (ECM) proteins include laminin-β1, perlecan, and collagen type IV-α2 and podocyte-specific ECM proteins include laminin-β2, agrin, and collagen type IV-α4. This study aimed to define individual ECM protein isoform expression by PECs in both experimental and human focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy (DN) and to determine if changes were CD44 dependent. In experimental FSGS induced with a cytotoxic podocyte antibody and in the BTBR ob/ob mouse model of DN, PEC-derived protein staining was significantly increased in PECs. Dual staining also showed de novo expression of the podocyte-specific ECM proteins laminin-β2 and agrin in PECs. Similar findings were observed in biopsies from patients with FSGS and DN. Increases in individual ECM proteins colocalized with CD44 in PECs in disease. To determine the role of CD44, FSGS was induced in CD44−/− and CD44+/+ mice. PEC staining for perlecan, collagen type IV-α2, laminin-β2, and agrin were significantly lower in diseased CD44−/− mice compared with diseased CD44+/+ mice. These results show that in experimental and human FSGS and DN, PECs typically in an activated state, produce both PEC-derived and podocyte-specific ECM protein isoforms, and that the majority of these changes were dependent on CD44.

scholarly journals Danggui buxue tang inhibited mesangial cell proliferation and extracellular matrix accumulation through GAS5/NF-κB pathway

2019 ◽  
Vol 39 (10) ◽  
Author(s):  
Rui Zhang ◽  
Xiao Han ◽  
Tao Huang ◽  
Xiuge Wang
Keyword(s):  
Extracellular Matrix ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Danggui Buxue Tang ◽  
Iκb Kinase ◽  
Non Coding Rna ◽  
The Common ◽  
Matrix Accumulation ◽  
Related Proteins ◽  
Long Non Coding Rna

Abstract Diabetic nephropathy (DN) is the common complications of diabetes mellitus, but the efficacy of available treatments for the prevention of DN is still unsatisfactory. In the present study, we aimed to explore the effect of Danggui buxue tang (DGT) on the proliferation of high glucose (HG)-induced mesangial cells and accumulation of extracellular matrix in mesangial cells. We found DGT up-regulated the expression of growth arrest specific transcript 5 (GAS5) and IκB kinase (IKK) dose-dependently in mouse mesangial cells (SV40 MES-13). We found DGT regulated the expression IKK and the activity of nuclear transcription factor-κB (NF-κB) via GAS5, and proved that long non-coding RNA (lncRNA) GAS5 was positively related with IKK. And we proved GAS5 regulated the expression of IKK and the activity of NF-κB. In addition, DGT inhibited the viability of MES-13 cells and extracellular matrix-related proteins (laminin (LN), fibronectin (FN) and collagen IV (Col IV)) via GAS5. Moreover, we proved GAS5 regulated the viability of SV40 MES-13 cells and extracellular matrix-related proteins through NF-κB pathway. DGT inhibited the proliferation of mesangial cells and accumulation of extracellular matrix via GAS5/NF-κB, therefore, DGT could be an effective treatment for the prevention of DN.

scholarly journals Parietal epithelial cells maintain the epithelial cell continuum forming Bowman's space in focal segmental glomerulosclerosis

2021 ◽  
Author(s):  
Laura Miesen ◽  
Péter Bándi ◽  
Brigith Willemsen ◽  
Fieke Mooren ◽  
Thiago Strieder ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Focal Segmental Glomerulosclerosis ◽  
Glomerular Epithelial Cell ◽  
Segmental Glomerulosclerosis ◽  
Glomerular Epithelial Cells ◽  
Tubular System ◽  
Sclerotic Lesions ◽  
Parietal Epithelial Cells ◽  
Glomerular Tuft

In the glomerulus, Bowman's space is formed by a continuum of glomerular epithelial cells. In focal segmental glomerulosclerosis (FSGS), glomeruli show segmental scarring, a result of activated PECs invading the glomerular tuft. The segmental scars interrupt the epithelial continuum. However, non-sclerotic segments seem to be preserved even in glomeruli with advanced lesions. We studied the histology of the segmental pattern in Munich Wistar Frömter (MWF) rats, a model for secondary FSGS. Our results showed that matrix layers lined with PECs cover the sclerotic lesions. These PECs formed contacts with podocytes of the uninvolved tuft segments, restoring the epithelial continuum. Formed Bowman's spaces were still connected to the tubular system. Furthermore, in biopsies of patients with secondary FSGS we also detected matrix layers formed by PECs, separating the uninvolved from the sclerotic glomerular segments. While PECs have a major role in the formation of glomerulosclerosis, we showed that in FSGS, PECs also restore the glomerular epithelial cell continuum that surrounds Bowman's space. This process may be beneficial and indispensable for glomerular filtration in the uninvolved segments of sclerotic glomeruli.

P0389THE PREVALENCE, CLINICAL AND PATHOLOGICAL CHARACTERISTICS OF PRIMARY FOCAL SEGMENTAL GLOMERULOSCLEROSIS IN TURKISH ADULTS: THE DATA FROM TSN-GOLD ( TURKISH SOCIETY OF NEPHROLOGY GLOMERULAR DISEASES) WORKING GROUP

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Ilhan Kurultak ◽  
Ozkan Gungor ◽  
Savas Ozturk ◽  
Ahmet Burak Dirim ◽  
Necmi Eren ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Nephrotic Syndrome ◽  
Focal Segmental Glomerulosclerosis ◽  
Pathological Examination ◽  
Glomerular Diseases ◽  
Segmental Glomerulosclerosis ◽  
Hospitalization Period ◽  
The Mean ◽  
Primary Glomerular Diseases ◽  
Turkish Society

Abstract Background and Aims Focal segmental glomerulosclerosis (FSGS) is one of the primary glomerulopathies which is the most common cause of end-stage renal disease among all primary glomerular diseases. In adults, nephrotic syndrome develops 10-35% due to FSGS. However, its frequency has been increasing in recent years. This study was aimed to present the data and the prevalence of primary FSGS patients in Turkey. Method These data were obtained from the National Multicenter (47 centers) Primary Glomerular Diseases registry system, which was entered into the Turkish Society of Nephrology Glomerular Diseases (TSN-GOLD) database between May 2009 and June 2019. The presented data in this study is cross-sectional and includes the recorded data of the patients in the hospitalization period for the kidney biopsy. These demographic, clinic and pathological data of patients were evaluated with using statistically. Results Of the 3875 patients enrolled in the Primary Glomerular Diseases database, 850 (21.9%) had FSGS. The mean age of the patients was 47.1 ± 13.7 and 435 (52%) of patients were male. Two hundred and eighty one (33.1%) had hypertension and 93 (11%) had diabetes. Five hundred and four patients (59.3%) were diagnosed as nephrotic syndrome. At the time of diagnosis, the mean systolic blood pressure was 13.8 ± 18.6 mm Hg and the mean diastolic blood pressure was 81.4± 11.4 mm Hg. The laboratory findings at the time of diagnosis on following; serum creatinine 1.2 ± 0.04 mg / dl, albumin 3.3 ± 0.03 g / dl, and 24 hours urinary proteinuria amounts to 4743 ± 181 mg / day. Demographical and clinical data of the patients at the time of diagnosis were presented on Table 1. In pathological examination; the mean number of glomeruli was 16.8 ± 0.3, global sclerotic glomeruli were 3.1 ± 0.1, and segmental sclerotic glomeruli were 2.4 ± 0.1. Summary of Pathological Findings were presented on Table 2 Conclusion It is very difficult to determine the absolute incidence and prevalence of primary FSGS. Incidence rates have been reported to range from 0.2 to 1.8 / 100,000 per year in the literature. In a United States study, the most common diagnosis in 2501 kidney biopsies was FSGS (35.9%). According to this database, the prevalence of FSGS in primary glomerular diseases in our country is 21.9%.

scholarly journals The Association between Glomerular Diameter and Secondary Focal Segmental Glomerulosclerosis in Chronic Kidney Disease

2021 ◽  
pp. 1-8
Author(s):  
Ryo Zamami ◽  
Kentaro Kohagura ◽  
Kojiro Kinjyo ◽  
Takuto Nakamura ◽  
Takanori Kinjo ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Biopsy ◽  
Focal Segmental Glomerulosclerosis ◽  
Characteristic Curve ◽  
Area Under The Curve ◽  
Glomerular Hypertrophy ◽  
Glomerular Lesion ◽  
Segmental Glomerulosclerosis ◽  
Glomerular Size

<b><i>Introduction:</i></b> When nephron loss occurs, the glomerular filtration rate (GFR) is suggested to be maintained by glomerular hypertrophy, but excessive hypertrophy can rather lead to the formation of focal segmental glomerulosclerosis (FSGS), thereby causing progressive kidney damage. However, it is not clear how much glomerular hypertrophy leads to the formation of FSGS. We examined the association between glomerular diameter and FSGS lesions in chronic kidney disease (CKD) patients. <b><i>Methods:</i></b> We recruited 77 patients who underwent renal biopsy during 2016–2017; however, those identified with primary FSGS and glomerulonephritis with active glomerular lesion were excluded. We evaluated the maximal glomerular diameter (Max GD), an indicator of glomerular size, in each renal biopsy specimen and examined its association with FSGS lesion. <b><i>Results:</i></b> The median age, blood pressure, and estimated GFR of the patients were 53 years, 122/70 mm Hg, and 65 mL/min/1.73 m<sup>2</sup>, respectively. The optimal cutoff threshold of Max GD for predicting the presence of FSGS lesions, assessed by receiver operating characteristic curve analysis, was determined to be at 224 μm (area under the curve, 0.81; sensitivity, 81%; specificity, 72%). Multivariate logistic regression analyses demonstrated that Max GD ≥224 μm was significantly associated with the presence of FSGS lesions, independent of other confounding factors (odds ratio, 11.70; 95% confidence interval, 1.93–70.84). <b><i>Discussion/Conclusion:</i></b> Glomerular hypertrophy (Max GD ≥224 μm) has been associated with FSGS lesions in CKD patients and may reflect the limits of the compensatory process.

Role of plasmin and gelatinase in extracellular matrix degradation by cultured rat mesangial cells

1992 ◽  
Vol 263 (6) ◽  
pp. F1112-F1118 ◽  
Author(s):  
A. P. Wong ◽  
S. L. Cortez ◽  
W. H. Baricos
Keyword(s):  
Extracellular Matrix ◽  
Mesangial Cells ◽  
Cell Number ◽  
Plasmin Activity ◽  
High Positive Correlation ◽  
Gelatinase Activity ◽  
Inactive Form ◽  
Ecm Degradation ◽  
Plasmin Inhibitors

We have examined the ability of mesangial cells (MCs) to degrade extracellular matrix (ECM) using cultured rat MCs grown on thin films of radiolabeled Matrigel. ECM degradation by cultured MCs was observed only in presence of exogenously added plasminogen and was a function of plasminogen concentration (0-50 mU), cell number (0-50,000 cells), and length of incubation (0-72 h). A high positive correlation (r > 0.93) was observed between ECM degradation and plasmin activity in medium, suggesting an important role for plasmin in ECM degradation by cultured MCs. This suggestion was confirmed by ability of plasmin inhibitors, alpha 2-antiplasmin (40 micrograms/ml) and aprotinin (216 kallikrein inhibition units/ml), to inhibit (> 90%) ECM degradation. Inhibitors of cysteine proteinases [trans-epoxysuccinyl-L-leucylamido(4-guanidino)butane, 10 microM] and aspartic proteinases (pepstatin, 5.0 micrograms/ml) had no effect on ECM degradation. However, in presence of plasminogen, inhibitors of matrix metalloproteinases, TIMP-1 (40 micrograms/ml) and o-phenanthroline (100 microM), inhibited ECM degradation -42 +/- 4% and -43 +/- 3% (SE), respectively (n = 8-10). Thus, in addition to plasmin, a matrix metalloproteinase(s) is also involved in ECM degradation by cultured rat MCs. Zymography of culture medium obtained from MCs grown on radiolabeled Matrigel films in absence of plasminogen revealed only two closely migrating bands of gelatinase activity, relative mol wt of approximately 70,000-72,000. MCs grown in absence of plasminogen failed to degrade ECM despite presence of gelatinase in medium, indicating that, in absence of plasmin, gelatinase is present in an inactive form, either as a latent proenzyme or as a gelatinase-inhibitor complex.(ABSTRACT TRUNCATED AT 250 WORDS)

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