Glucose enhances mesangial cell apoptosis

Khera, Tarnjit K.; Martin, John T.; Riley, Stephen; Steadman, Robert; Phillips, Aled Owain

doi:10.1038/labinvest.3700418

Cited by 49 publications

(48 citation statements)

References 54 publications

(57 reference statements)

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“…Mesangial cell response to pathological stimuli is associated with the main events of glomerular injury and is important for resistance to glycoxidative stress through an antioxidant response (6). A previous study reported that alterations in glucose associated with diabetes mellitus induce mesangial cell apoptosis and contribute to diabetic nephropathy (7). However, the mechanism by which mesangial cell apoptosis is regulated in diabetic individuals remains unclear.…”

Section: Introductionmentioning

confidence: 99%

C/EBP homologous protein induces mesangial cell apoptosis under hyperglycemia

Zhao

et al. 2012

Molecular Medicine Reports

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Abstract. Diabetes mellitus is known to cause kidney impairment; however, the mechanism remains elusive. The aim of this study was to investigate the role of C/EBP homologous protein (CHOP), an important protein in endoplasmic reticulum stress-mediated mesangial cell apoptosis in hyperglycemia. Mesangial cells were cultured in normal (control group) and high glucose medium (high glucose group). TUNEL staining was performed to assess apoptotic cells in the groups. The expression of CHOP and caspase-3 was also assayed by immunohistochemistry and western blot analysis. Following 24 h culture in high glucose medium, TUNEL-positive cells were observed to be significantly increased (P<0.01). The expression of CHOP and caspase-3 in mesangial cells was also found to be significantly enhanced under high glucose conditions compared with the normal group (P<0.01). The results indicate that CHOP mediates apoptosis in mesangial cells under hyperglycemia and may play a role in the development of diabetic nephropathy.

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Section: Introductionmentioning

confidence: 99%

C/EBP homologous protein induces mesangial cell apoptosis under hyperglycemia

Zhao

et al. 2012

Molecular Medicine Reports

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“…In an environment of high glucose (HG), renal mesangial cells undergo cascades of deleterious reactions, including cell injury and extracellular matrix deposition, which lead to glomeruli dysfunction (1,25,49). Mesangial cell apoptosis promoted by HG contributes to the development of diabetic nephropathy (22,40).…”

Section: Shmentioning

confidence: 99%

Cannabinoid receptor 1 mediates high glucose-induced apoptosis via endoplasmic reticulum stress in primary cultured rat mesangial cells

Lim

Park

et al. 2011

American Journal of Physiology-Renal Physiology

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SH.Cannabinoid receptor 1 mediates high glucose-induced apoptosis via endoplasmic reticulum stress in primary cultured rat mesangial cells. Am J Physiol Renal Physiol 301: F179 -F188, 2011. First published February 16, 2011 doi:10.1152/ajprenal.00032.2010.-The endocannabinoid system in animals and humans is involved in the onset of diverse diseases, including obesity and diabetic nephropathy, which is a major end-stage renal disease characterized by high glucose (HG)-induced apoptosis of mesangial cells. Endocannabinoids induce physiological and behavioral effects by activating two specific receptors, cannabinoid receptor 1 (CB 1R) and cannabinoid receptor 2 (CB2R). However, the pathophysiology of CB 1R in diabetic nephropathy has not been elucidated. We investigated the effects of HG on CB 1R expression and its signaling pathways in primary cultured rat mesangial cells. HG significantly increased CB 1R mRNA and protein levels in a time-dependent manner and induced CB 1R internalization. NF-B and cPLA 2 were involved in the HG-induced increase in CB 1R levels. Using a CB1R antagonist (AM251) and CB1 siRNA transfection, we showed that HG-induced CB 1R is linked to apoptosis. Specifically, HG inhibited the expression of GRP78, but induced increases in endoplasmic reticulum (ER) stress proteins, including phosphorylated (p)-protein kinase-like ER-associated kinase, p-eukaryotic initiation factor 2␣, p-activating transcription factor-4, and C/EBP homologous protein. In addition, HG increased the Bax/Bcl-2 ratio and increased the amounts of cleaved poly(ADP-ribose) polymerase and caspase-3. These apoptotic effects were prevented by AM251 and by the downregulation of CB 1R expression by small interfering RNA. We propose a mechanism by which blockade of CB 1R attenuates HG-induced apoptosis in rat mesangial cells. Our findings suggest that blockade of CB 1R may be a potential therapy in diabetic nephropathy. endocannabinoid system DIABETIC NEPHROPATHY IS CHARACTERIZED by hyperglycemia-induced dysfunction of mesangial cells (21). In an environment of high glucose (HG), renal mesangial cells undergo cascades of deleterious reactions, including cell injury and extracellular matrix deposition, which lead to glomeruli dysfunction (1,25,49). Mesangial cell apoptosis promoted by HG contributes to the development of diabetic nephropathy (22,40).Endocannabinoids are endogenous lipid mediators with a wide range of biological effects, similar to those of marijuana. The endocannabinoid system (ECS) regulates synaptic plasticity, emotional responses, energy homeostasis, and glucose metabolism (44). Dysregulation of ECS is involved in the onset of obesity and diabetic nephropathy (12). Barutta et al. (5) have reported that cannabinoid receptor 1 (CB 1 R) was overexpressed within glomeruli in diabetic mice and CB 1 blockade prevented diabetes-induced albuminuria. It has been also reported that the condition of HG increased the endogenous ligands of the ECS, N-arachidonoyl ethanolamine (AEA) and 2-arachidonylglycerol ( 2-AG) in vivo...

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“…11,12 Mesangial cell apoptosis can further promote the development of DN. [13][14][15] As DN progresses, ECM, which includes collagen IV, is deposited in the mesangium, causing gradual obliteration of glomerular capillary loops and progressive decline in glomerular filtration. 16 Mitochondria are the essential organelle in cell life and death, whose damage endangers lipid protein synthesis, cell oxidative phosphorylation, ATP production in cell metabolism and regulation of cellular steady state.…”

Section: Introductionmentioning

confidence: 99%

Inhibition to DRP1 translocation can mitigate p38 MAPK-signaling pathway activation in GMC induced by hyperglycemia

Zhang

Tang

et al. 2015

Renal Failure

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Diabetic nephropathy (DN) is a serious complication of diabetes with a poorly defined etiology and limited treatment options. Early intervention is a key to preventing the progression of DN. Dynamin-related protein 1 (DRP1) regulates mitochondrial morphology by promoting its fission and is involved in the pathogenesis of numerous diseases. Furthermore, DRP1 is also closely associated with the development of diabetes, but its functional role in DN remains unknown. This study investigated the effect of DRP1 on early stage of DN. DRP1 expression has increased significantly in glomerular mesangial cell (GMC), which is cultivated in high glucose (HG). Ultramicrostructural changes of nephrons, expression of collagen IV and phosph-p38, ROS production, and mitochondrial function were evaluated and, at the same time, were compared with glomerular mesangial cell (GMC) cultured in normal-glucose (NG), mannitol, and a medium with mitochondrial division inhibitor 1 (Midivi-1). Endogenous DRP1 expression increased in DN. Compared to the control groups ofNG and mannitol, overexpression of DRP1 destroyed pathological changes typical of the GMC, like accumulation of extracellular matrix, and an increase in mitochondria division. In addition, Overexpression of DRP1 promoted the activation of p38, the accumulation of ROS, mitochondrial dysfunction, and the synthesis of collagen IV, and all these changes are suppressed by Midivi-1. This study demonstrates that DRP1 overexpression can accelerate pathological changes in the GMC cultured in HG. Further studies are needed to clarify the underlying mechanism of this destructive function.

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Glucose enhances mesangial cell apoptosis

Cited by 49 publications

References 54 publications

C/EBP homologous protein induces mesangial cell apoptosis under hyperglycemia

C/EBP homologous protein induces mesangial cell apoptosis under hyperglycemia

Cannabinoid receptor 1 mediates high glucose-induced apoptosis via endoplasmic reticulum stress in primary cultured rat mesangial cells

Inhibition to DRP1 translocation can mitigate p38 MAPK-signaling pathway activation in GMC induced by hyperglycemia

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