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.

Glomerular mesangial cell adhesion to fibrinogen is mediated by αvβ3 integrin

2004 ◽  
Vol 82 (5) ◽  
pp. 597-601 ◽  
Author(s):  
Edgar G Fischer
Keyword(s):  
Extracellular Matrix ◽  
Cell Adhesion ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Extracellular Matrix Proteins ◽  
Matrix Proteins ◽  
Biological Behavior ◽  
Αvβ3 Integrin ◽  
Glomerular Mesangial Cells ◽  
Mesangioproliferative Glomerulonephritis

The biological behavior of glomerular mesangial cells is thought to play a critical role in human and experimental forms of mesangioproliferative glomerulonephritis. In these diseases, mesangial cells proliferate and produce increased amounts of extracellular matrix proteins, which can lead to glomerulosclerosis and end-stage renal disease. Mesangial cells interact with extracellular matrix proteins through integrin-mediated cell adhesion. Fibrinogen as a plasma-derived protein is known to be deposited in the mesangium of kidneys affected by mesangioproliferative glomerulonephritis. The adhesive interactions between fibrinogen and mesangial cells, however, have not been reported. Results in this work show that mesangial cells adhere to immobilized fibrinogen in an integrin-dependent fashion. This process was inhibited by the αvβ3-selective peptide cyclo-RGDFV and the monoclonal anti-β3 integrin chain antibody F11. Ca2+ ions are a known strong inhibitor of the fibrinogen-αvβ3 interaction, and mesangial cell adhesion did not occur when Ca2+ was the only divalent cation present. Therefore, mesangial cell adhesion to fibrinogen is mediated by αvβ3 integrin, and divalent cations have a fundamental role in regulating this process.Key words: glomerular mesangial cells, adhesion, extracellular matrix, fibrinogen, integrins, αvβ3.

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 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 The cyclin kinase inhibitor p21WAF1, CIP1 is increased in experimental diabetic nephropathy: potential role in glomerular hypertrophy.

1998 ◽  
Vol 9 (6) ◽  
pp. 986-993 ◽  
Author(s):  
C J Kuan ◽  
M al-Douahji ◽  
S J Shankland
Keyword(s):  
Cell Cycle ◽  
Diabetic Nephropathy ◽  
High Glucose ◽  
Mesangial Cell ◽  
Kinase Inhibitor ◽  
Glomerular Hypertrophy ◽  
Glomerular Cell ◽  
Cyclin Dependent Kinases ◽  
Cell Hypertrophy

High glucose inhibits mesangial cell proliferation in vitro and induces hypertrophy in mesangial cells in culture and in experimental diabetic nephropathy. Cell growth is ultimately controlled at the level of the cell cycle by cell cycle regulatory proteins. Cell cycle progression requires that cyclin-dependent kinases be activated by cyclins. Cyclin kinase inhibitors (CKI) inactivate cyclin-dependent kinases, causing cell cycle arrest. In the current study, high glucose-induced mesangial cell hypertrophy in vitro is shown to be associated with increased levels of the CKI p21, but not p27. In the streptozotocin model of experimental diabetes in the mouse, glomerular hypertrophy was associated with a selective increase in p21 expression, whereas the levels of the CKI p27 and p57 did not change. Unlike many other forms of glomerular injury, diabetic nephropathy was not associated with increased apoptosis. These results support a role for p21 in causing glomerular cell hypertrophy in diabetic nephropathy.

Thromboxane stimulates synthesis of extracellular matrix proteins in vitro

1991 ◽  
Vol 261 (3) ◽  
pp. F488-F494 ◽  
Author(s):  
L. A. Bruggeman ◽  
E. A. Horigan ◽  
S. Horikoshi ◽  
P. E. Ray ◽  
P. E. Klotman
Keyword(s):  
Extracellular Matrix ◽  
Matrix Protein ◽  
Mesangial Cells ◽  
Extracellular Matrix Proteins ◽  
Cellular Protein ◽  
Matrix Proteins ◽  
Extracellular Matrix Protein ◽  
Renal Diseases ◽  
Glomerular Mesangial Cells

The vasoconstrictor eicosanoid thromboxane plays an important role in the pathogenesis of several renal diseases. As an autacoid, its local release alters blood flow and induces platelet aggregation. We report a direct stimulatory effect of thromboxane on extracellular matrix protein production and gene expression in vitro. Treatment of two cell types, differentiated mouse teratocarcinoma cells (F9+) and human glomerular mesangial cells, with two different thromboxane analogues resulted in increased production of components of the extracellular matrix including fibronectin and the basement membrane proteins laminin and type IV collagen. These responses to thromboxane were not the result of a mitogenic effect of thromboxane nor the result of an increase in total cellular protein. The increased production of extracellular matrix proteins was, at least in part, due to an increase in the steady-state level of mRNA for these genes. Furthermore, the effect of thromboxane was markedly inhibited by cotreatment with a thromboxane-receptor antagonist. These results suggest a new potential role for thromboxane as a mediator of the sclerotic and fibrotic responses to injury.

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