High glucose promotes mesangial cell apoptosis by oxidant-dependent mechanism

2003 ◽  
Vol 284 (3) ◽  
pp. F455-F466 ◽  
Author(s):  
Barinder P. S. Kang ◽  
Stanley Frencher ◽  
Venkatesh Reddy ◽  
Alex Kessler ◽  
Ashwani Malhotra ◽  
...  
Keyword(s):  
High Glucose ◽  
Glucose Concentration ◽  
Cell Apoptosis ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Oxidant Stress ◽  
Binding Activity ◽  
Biological Responses ◽  
Proapoptotic Protein ◽  
Dependent Mechanism

Reactive oxygen species are recognized as important mediators of biological responses. Hyperglycemia promotes the intracellular generation of superoxide anion and hydrogen peroxide. In several cell lines, oxidant stress has been linked to the activation of death programs. Here, we report for the first time that high ambient glucose concentration induces apoptosis in murine and human mesangial cells by an oxidant-dependent mechanism. The signaling cascade activated by glucose-induced oxidant stress included the heterodimeric redox-sensitive transcription factor NF-κB, which exhibited an upregulation in p65/c-Rel binding activity and suppressed binding activity of the p50 dimer. Recruitment of NF-κB and mesangial cell apoptosis were both inhibited by antioxidants, implicating oxidant-induced activation of NF-κB in the transmission of the death signal. The genetic program for glucose-induced mesangial cell apoptosis was characterized by an upregulation of the Bax/Bcl-2 ratio. In addition, phosphorylation of the proapoptotic protein Bad was attenuated in mesangial cells maintained at high-glucose concentration, favoring progression of the apoptotic process. These perturbations in the expression and phosphorylation of the Bcl-2 family were coupled with the release of cytochrome c from mitochondria and caspase activation. Our findings indicate that in mesangial cells exposed to high ambient glucose concentration, oxidant stress is a proximate event in the activation of the death program, which culminates in mitochondrial dysfunction and caspase-3 activation, as the terminal event.

scholarly journals Superoxide Destabilization of β-Catenin Augments Apoptosis of High-Glucose-Stressed Mesangial Cells

Endocrinology ◽  
2008 ◽  
Vol 149 (6) ◽  
pp. 2934-2942 ◽  
Author(s):  
Chun-Liang Lin ◽  
Jeng-Yi Wang ◽  
Jih-Yang Ko ◽  
Kameswaran Surendran ◽  
Yu-Ting Huang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Superoxide Dismutase ◽  
High Glucose ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Renal Tissue ◽  
Dominant Negative ◽  
Gsk 3Β

Intense mesangial cell apoptosis contributes to the pathogenesis of diabetic nephropathy. Although reactive oxygen radicals and Wnt signaling components are potent regulators that modulate renal tissue remodeling and morphogenesis, cross-talk between oxidative stress and Wnt/β-catenin signaling in controlling high-glucose-impaired mesangial cell survival and renal function have not been tested. In this study, high glucose induced Ras and Rac1 activation, superoxide burst, and Wnt5a/β-catenin destabilization and subsequently promoted caspase-3 and poly (ADP-ribose) polymerase cleavage and apoptosis in mesangial cell cultures. The pharmacological and genetic suppression of superoxide synthesis by superoxide dismutase and diphenyloniodium, dominant-negative Ras (S17N), and dominant-negative Rac1 (T17N) abrogated high-glucose-induced glycogen synthase kinase (GSK-3β) activation and caspase-3 and poly (ADP-ribose) polymerase degradation. Inactivation of Ras and Racl also reversed Wnt/β-catenin expression and survival of mesangial cells. Stabilization of β-catenin by the transfection of stable β-catenin (Δ45) and kinase-inactive GSK-3β attenuated high-glucose-mediated mesangial cell apoptosis. Exogenous superoxide dismutase administration attenuated urinary protein secretion in diabetic rats and abrogated diabetes-mediated reactive oxygen radical synthesis in renal glomeruli. Immunohistological observation revealed that superoxide dismutase treatment abrogated diabetes-induced caspase-3 cleavage and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) and increased Wnt5a/β-catenin expression in renal glomeruli. Taken together, high glucose induced oxidative stress and apoptosis in mesangial cells. The Ras and Rac1 regulation of superoxide appeared to raise apoptotic activity by activating GSK-3β and inhibiting Wnt5a/β-catenin signaling. Controlling oxidative stress and Wnt/β-catenin signaling has potential for protecting renal tissue against the deleterious effect of high glucose.

scholarly journals High glucose inhibits nitric oxide production in cultured rat mesangial cells.

1997 ◽  
Vol 8 (8) ◽  
pp. 1276-1282
Author(s):  
H Trachtman ◽  
S Futterweit ◽  
D L Crimmins
Keyword(s):  
Nitric Oxide ◽  
High Glucose ◽  
Glucose Concentration ◽  
Transforming Growth Factor ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Guanosine Monophosphate ◽  
Time Dependent ◽  
No Production ◽  
Dependent Manner

Hyperglycemia directly contributes to the development of diabetic nephropathy. A high-serum glucose concentration alters intraglomerular hemodynamics and promotes deposition of extracellular matrix in the kidney. Nitric oxide (NO) is a short-lived messenger molecule that participates in the regulation of renal blood flow, GFR, and mesangial matrix accumulation. Therefore, in this study it was tested whether high glucose directly modulates NO synthesis by rat mesangial cells in vitro by measuring the accumulation of nitrite, the stable metabolite of NO, in the incubation media. Raising the external glucose concentration to 33.3 mM for 24 to 72 h reduced nitrite levels in cell supernatants in a time-dependent manner to a nadir of 14 +/- 3% of the amount in normal glucose media (5.6 mM) (P < 0.01). The decline in NO synthesis in high glucose media was paralleled by decreased cyclic guanosine monophosphate generation; however, there was no alteration in rat mesangial cell expression of inducible NO synthase protein. The suppressive effect of high glucose on NO production by mesangial cells was not modified by inhibition of protein kinase C (H-7), the addition of antioxidants (vitamin E or superoxide dismutase), or a pan-specific anti-transforming growth factor-beta antibody. An elevated ambient glucose caused a time-dependent reduction in mesangial cell L-arginine content. Addition of L-arginine (10 to 20 mM) to external media partially reversed the inhibitory effect of high glucose on mesangial cell NO production in a dose-dependent manner. The highest dose of L-arginine (20 mM) increased mesangial cell L-arginine content to comparable levels in normal and high glucose media. These results indicate that high glucose causes depletion of L-arginine in mesangial cells and compromises NO synthesis. Limitation in the metabolic precursor and other, as yet unidentified, factors act to reduce NO production by mesangial cells in the presence of an elevated ambient glucose level, a change that may play a role in the development of diabetic glomerulosclerosis.

scholarly journals High Glucose Induces Mesangial Cell Apoptosis through miR-15b-5p and Promotes Diabetic Nephropathy by Extracellular Vesicle Delivery

2020 ◽  
Vol 28 (3) ◽  
pp. 963-974 ◽  
Author(s):  
Yi-Chun Tsai ◽  
Mei-Chuan Kuo ◽  
Wei-Wen Hung ◽  
Ling-Yu Wu ◽  
Ping-Hsun Wu ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
High Glucose ◽  
Cell Apoptosis ◽  
Mesangial Cell ◽  
Extracellular Vesicle

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.

The Actions of C-Type Natriuretic Peptide on Human Mesangial Cell Apoptosis and P53 Expression

2000 ◽  
Vol 6 (S2) ◽  
pp. 624-625
Author(s):  
K. Seta ◽  
C. Wei
Keyword(s):  
Receptor Antagonist ◽  
Natriuretic Peptide ◽  
Cell Apoptosis ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Endocrine System ◽  
P53 Gene ◽  
Glomerular Mesangial Cells ◽  
P53 Expression ◽  
Human Mesangial Cell

C-type natriuretic peptide (CNP) of endothelial cell origin via NPR-B receptor mediates antimitogenic and vasodilatory actions. As a circulating endocrine system, CNP plays a fundamental role in cardiorenal regulation. However, the actions of CNP on renal mesangial cell apoptosis remain poorly defined. Apoptosis might plays an important role during development of renal glomerular mesangial cells pathophysiology. The mechanisms of apoptosis include p53-dependent pathway and p53-independent pathway.The hypothesis of this study is that CNP induces apoptosis through the process involving p53 gene in human glomerular mesangial cells via natriuretic peptide biological receptor. Therefore, the current study was designed to investigate the effects of CNP on apoptosis and p53 expression in human mesangial cell in the absence or presence of CNP biological receptor antagonist.Cultured human mesangial cells (Clontech Lab., San Diego, CA) was incubated for 24 hours in the absence or presence of CNP (10-7 M). These studies were repeated with HS 142-1 (HS, 10-5 M), a CNP biological receptor antagonist.

scholarly journals BKCa Mediates Dysfunction in High Glucose Induced Mesangial Cell Injury via TGF-β1/Smad2/3 Signaling Pathways

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Zhigui Wu ◽  
Wenxian Yin ◽  
Mengqi Sun ◽  
Yuankai Si ◽  
Xiaoxiao Wu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Kidney Disease ◽  
Signaling Pathways ◽  
Transforming Growth Factor Beta ◽  
High Glucose ◽  
Diabetic Kidney Disease ◽  
Transforming Growth Factor ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Diabetic Kidney

Objective. To explore the role and mechanism of BKCa in diabetic kidney disease. Methods. Rat mesangial cells (MCs) HBZY-1 were cultured with high glucose to simulate the high-glucose environment of diabetic kidney disease in vivo. The effects of large conductance calcium-activated potassium channel (BKCa) on proliferation, migration, and apoptosis of HBZY-1 cells were observed. The contents of transforming growth factor beta 1 (TGF-β1), Smad2/3, collagen IV (Col IV), and fibronectin (FN) in the extracellular matrix were also observed. Results. High glucose significantly damaged HBZY-1 cells, which enhanced the ability of cell proliferation, migration, and apoptosis, and increased the secretion of Col IV and FN. Inhibition of BKCa and TGF-β1/Smad2/3 signaling pathways can inhibit the proliferation, migration, and apoptosis of HBZY-1 cells and suppress the secretion of Col IV and FN. The effect of excitation is the opposite. Conclusions. BKCa regulates mesangial cell proliferation, migration, apoptosis, and secretion of Col IV and FN and is associated with TGF-β1/Smad2/3 signaling pathway.

scholarly journals Regulation of angiotensin II receptors and PKC isoforms by glucose in rat mesangial cells

1999 ◽  
Vol 276 (5) ◽  
pp. F691-F699 ◽  
Author(s):  
Farhad Amiri ◽  
Raul Garcia
Keyword(s):  
Angiotensin Ii ◽  
High Glucose ◽  
Glucose Concentration ◽  
Mesangial Cells ◽  
Competitive Binding ◽  
Ang Ii ◽  
Pkc Isoforms ◽  
Normal Glucose ◽  
Elevated Glucose ◽  
In Cells

It has been shown that glomerular angiotensin II (ANG II) receptors are downregulated and protein kinase C (PKC) is activated under diabetic conditions. We, therefore, investigated ANG II receptor and PKC isoform regulation in glomerular mesangial cells (MCs) under normal and elevated glucose concentrations. MCs were isolated from collagenase-treated rat glomeruli and cultured in medium containing normal or high glucose concentrations (5.5 and 25.0 mM, respectively). Competitive binding experiments were performed using the ANG II antagonists losartan and PD-123319, and PKC analysis was conducted by Western blotting. Competitive binding studies showed that the AT1 receptor was the only ANG II receptor detected on MCs grown to either subconfluence or confluence under either glucose concentration. AT1 receptor density was significantly downregulated in cells grown to confluence in high-glucose medium. Furthermore, elevated glucose concentration enhanced the presence of all MC PKC isoforms. In addition, PKCβ, PKCγ and PKCε were translocated only in cells cultured in elevated glucose concentrations following 1-min stimulation by ANG II, whereas PKCα, PKCθ, and PKCλ were translocated by ANG II only in cells grown in normal glucose. Moreover, no changes in the translocation of PKCδ, PKCι, PKCζ, and PKCμ were detected in response to ANG II stimulation under euglycemic conditions. We conclude that MCs grown in high glucose concentration show altered ANG II receptor regulation as well as PKC isoform translocation compared with cells grown in normal glucose concentration.

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