High glucose induced endothelial cell growth inhibition is associated with an increase in TGFβ1 secretion and inhibition of Ras prenylation via suppression of the mevalonate pathway

Mather, Amanda; Chen, X.M.; McGinn, Stella; Field, M.J.; Sumual, Siska; Mangiafico, Salvatore; Zhang, Y.; Kelly, Darren J.; Pollock, Carol

doi:10.1016/j.biocel.2008.07.007

Cited by 4 publications

(3 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To interpret this paradoxical observation, we speculate that RAGE-mediated activation of the pro-inflammatory ERK1/2/cPLA2 axis can be significantly potentiated by the VEGF-A signaling, as indicated by increased phosphorylation levels in both ERK1/2 and cPLA2 following treatment with HG plus VEGF-A. However, we cannot exclude that in cells subjected to both HG and exogenous VEGF-A, an additional cPLA2 phosphorylation occurs at Ser 505 by p38 MAP kinase, as described in different cell system [41,[58][59][60]. In addition, in cells treated with both HG and exogenous VEGF-A we observed an upregulation of iPLA2 protein expression; the ensuing increase in enzymatic activity might further contribute to cell damage and/or impairment of angiogenic effects of VEGF-A.…”

Section: Discussionmentioning

confidence: 99%

Activation of the VEGF-A/ERK/PLA2 Axis Mediates Early Retinal Endothelial Cell Damage Induced by High Glucose: New Insight from an In Vitro Model of Diabetic Retinopathy

Giurdanella

Lupo

Gennuso

et al. 2020

IJMS

View full text Add to dashboard Cite

Early blood retinal barrier (BRB) dysfunction induced by hyperglycemia was related to increased pro-inflammatory activity of phospholipase A2 (PLA2) and the upregulation of vascular endothelial growth factor A (VEGF-A). Here, we tested the role of VEGF-A in high glucose (HG)-induced damage of human retinal endothelial cells (HRECs) mediated by Ca++-dependent (cPLA2) and Ca++-independent (iPLA2) PLA2s. HRECs were treated with normal glucose (5 mM, NG) or high glucose (25 mM, HG) for 48 h with or without the VEGF-trap Aflibercept (Afl, 40 µg/mL), the cPLA2 inhibitor arachidonoyl trifluoromethyl ketone (AACOCF3; 15 µM), the iPLA2 inhibitor bromoenol lactone (BEL; 5 µM), or VEGF-A (80 ng/mL). Both Afl and AACOCF3 prevented HG-induced damage (MTT and LDH release), impairment of angiogenic potential (tube-formation), and expression of VEGF-A mRNA. Furthermore, Afl counteracted HG-induced increase of phospho-ERK and phospho-cPLA2 (immunoblot). VEGF-A in HG-medium increased glucose toxicity, through upregulation of phospho-ERK, phospho-cPLA2, and iPLA2 (about 55%, 45%, and 50%, respectively); immunocytochemistry confirmed the activation of these proteins. cPLA2 knockdown by siRNA entirely prevented cell damage induced by HG or by HG plus VEGF-A, while iPLA2 knockdown produced a milder protective effect. These data indicate that VEGF-A mediates the early glucose-induced damage in retinal endothelium through the involvement of ERK1/2/PLA2 axis activation.

show abstract

Section: Discussionmentioning

confidence: 99%

Activation of the VEGF-A/ERK/PLA2 Axis Mediates Early Retinal Endothelial Cell Damage Induced by High Glucose: New Insight from an In Vitro Model of Diabetic Retinopathy

Giurdanella

Lupo

Gennuso

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…Early tubular injury has been reported in patients with diabetes mellitus whose glomerular function is intact [25] and tubulointerstitial injury has been recognized to correlate more closely than glomerular pathology with functional abnormalities [26], [27]. The epithelial cells of the proximal tubule are hence considered as major players in orchestrating renal interstitial fibrosis in diabetic nephropathy, with both hyperglycaemia [19], [20], [28], [29], [30], [31], [32], [33] and hypoxia [25], [34], [35], [36] considered to be the major initiators of cellular pathology.…”

Section: Discussionmentioning

confidence: 99%

Plumbagin Ameliorates Diabetic Nephropathy via Interruption of Pathways that Include NOX4 Signalling

et al. 2013

View full text Add to dashboard Cite

NADPH oxidase 4 (Nox4) is reported to be the major source of reactive oxygen species (ROS) in the kidneys during the early stages of diabetic nephropathy. It has been shown to mediate TGFβ1-induced differentiation of cardiac fibroblasts into myofibroblasts. Despite TGFβ1 being recognised as a mediator of renal fibrosis and functional decline role in diabetic nephropathy, the renal interaction between Nox 4 and TGFβ1 is not well characterised. The aim of this study was to investigate the role of Nox4 inhibition on TGFβ1-induced fibrotic responses in proximal tubular cells and in a mouse model of diabetic nephropathy. Immortalised human proximal tubular cells (HK2) were incubated with TGFβ1 ± plumbagin (an inhibitor of Nox4) or specific Nox4 siRNA. Collagen IV and fibronectin mRNA and protein expression were measured. Streptozotocin (STZ) induced diabetic C57BL/6J mice were administered plumbagin (2 mg/kg/day) or vehicle (DMSO; 50 µl/mouse) for 24 weeks. Metabolic, physiological and histological markers of nephropathy were determined. TGFβ1 increased Nox4 mRNA expression and plumbagin and Nox4 siRNA significantly inhibited TGF-β1 induced fibronectin and collagen IV expression in human HK2 cells. STZ-induced diabetic C57BL/6J mice developed physiological features of diabetic nephropathy at 24 weeks, which were reversed with concomitant plumbagin treatment. Histologically, plumbagin ameliorated diabetes induced upregulation of extracellular matrix protein expression compared to control. This study demonstrates that plumbagin ameliorates the development of diabetic nephropathy through pathways that include Nox4 signalling.

show abstract

“…One of the possibilities is hypoprenylation of Rho, Ras, Raf and other small G-proteins normally involved in intracellular signal transduction in Mf proinflammatory response. There are reports confirming the link between hypoprenylation and the increase of TGF-β1 expression and secretion in endothelial cells [18], in embryonic heart cells [19] and in some other cell types [20,21,22], although the role of hypoprenylation in TGF-β1 secretion in Mf remains to be confirmed.…”

Section: Discussionmentioning

confidence: 98%

Cholesterol-Induced Impact on Murine Macrophage Responsiveness Involves down-Regulation of Mevalonate Pathway

Schwartz¹,

Dolganova²,

Чересиз³

2014

View full text Add to dashboard Cite

Free cholesterol (Ch) and its oxidative derivatives, oxysterols, are often accumulated in macrophages during chronic inflammation and atherogenesis. The effects of Ch and oxysterols on the balance of pro-and anti-inflammatory cytokines in inflammatory response and the role of mevalonate pathway in the effects of these sterols are studied poorly. We studied the effects of cholesterol, oxysterols, atorvastatin, and mevalonic acid on the LPS-induced TNF-α, IL-10, and TGF-β1 production in macrophage cell culture. The study was carried out in murine peritoneal macrophages preincubated for 4 h with Ch (5 µg/mL), 25-hydroxycholesterol (25-OH-Ch) (5 µg/mL), 7-keto-Ch (5 µg/mL), farnesol (10 µM), or atorvastatin (5 µmol/mL) in the presence or absence of 1 mM of mevalonate. The cells were further incubated in the presence or absence of E. coli 0111:B4 lipopolysaccharide (LPS) for 24 h, and cytokine concentrations in incubation media were determined. Macrophages preincubation with Ch, 25-OH-Ch, or atorvastatin decreased LPS-induced TNF-α production in cell cultures, while supplementation of preincubation medium with mevalonic acid abrogated the effects of atorvastatin and Ch. The Ch, 25-OH-Ch, 7-keto-Ch and atorvastatin significantly reduced IL-10 production by LPS-stimulated macrophages, while farnesol had no effect. Supplementation of Ch or atorvastatin-containing preincubation medium with mevalonate restored IL-10 production. The TGF-β1 production was significantly enhanced by the presence of Ch or atorvastatin in preincubation medium as compared to the control level in non-treated macrophages, while 25-OH-Ch or farnesol decreased profoundly TGF-β1 production. Mevalonate abrogated the effect of Ch or atorvastatin but not of 25-OH-Ch or farnesol. These results allow to conclude, that Ch is able to promote anti-inflammatory and fibrogenic macrophage response, which is connected, at least in part, with the deficiency of mevalonate pathway intermediates, particularly to the deficiency of farnesol, whereas hydroxysterols produce tolerogenic, but not fibrogenic effect, independently of mevalonate pathway.

show abstract

High glucose induced endothelial cell growth inhibition is associated with an increase in TGFβ1 secretion and inhibition of Ras prenylation via suppression of the mevalonate pathway

Cited by 4 publications

References 46 publications

Activation of the VEGF-A/ERK/PLA2 Axis Mediates Early Retinal Endothelial Cell Damage Induced by High Glucose: New Insight from an In Vitro Model of Diabetic Retinopathy

Activation of the VEGF-A/ERK/PLA2 Axis Mediates Early Retinal Endothelial Cell Damage Induced by High Glucose: New Insight from an In Vitro Model of Diabetic Retinopathy

Plumbagin Ameliorates Diabetic Nephropathy via Interruption of Pathways that Include NOX4 Signalling

Cholesterol-Induced Impact on Murine Macrophage Responsiveness Involves down-Regulation of Mevalonate Pathway

Contact Info

Product

Resources

About