当前位置： SCI文献检索 > DIABETOLOGIA期刊下所有文献 > Collagen I induction by high glucose levels is mediated by epidermal growth factor receptor and phosphoinositide 3-kinase/Akt signalling in mesangial cells.

Collagen I induction by high glucose levels is mediated by epidermal growth factor receptor and phosphoinositide 3-kinase/Akt signalling in mesangial cells.

Abstract：

AIMS/HYPOTHESIS:Glomerular matrix accumulation is a hallmark of diabetic nephropathy. Recent data have linked the serine/threonine kinase protein kinase B (Akt) to matrix modulation. Here, we studied its role in high glucose-induced collagen elaboration by mesangial cells. METHODS:Primary rat mesangial cells were treated with high glucose levels (30 mmol/l) or mannitol as osmotic control. Western blots, northern blots, ELISA and immunohistochemistry were used for assessment. Diabetes was induced in rats by streptozotocin. RESULTS:Phosphorylated Akt at S473 (pAktS473), corresponding to Akt activation, was seen in diabetic glomeruli. In mesangial cells, high glucose levels induced pAktS473 by 20 min. This was sustained to 72 h, while mannitol had no effect. Akt activation by kinase assay and phosphorylation on threonine 308 was also observed. Phosphoinositide 3-kinase (PI3K) inhibitors LY294002 (20 micromol/l) and wortmannin (100 nmol/l) prevented pAktS473. Collagen IA1 transcript and collagen I protein upregulation by high glucose levels were inhibited by PI3K blockade, as was collagen I secretion into the medium (ELISA). Dominant-negative Akt overexpression also inhibited high glucose-induced collagen IA1 transcript and collagen I protein production. Since signalling through the epidermal growth factor receptor (EGFR) can activate PI3K-Akt, we studied its activation by high glucose levels. EGFR was correspondingly activated by 10 min; mannitol had no effect. EGFR activation was also seen in glomeruli from diabetic rats and co-localised with collagen IA1 in diabetic glomeruli. Specific EGFR inhibition (AG1478, 5 micromol/l or dominant-negative EGFR) blocked high glucose-induced pAktS473, phosphorylation on threonine 308 and activation of the EGFR downstream target p44 extracellular signal-regulated kinase (Erk) mitogen-activated protein kinase. Finally, EGFR inhibition also blocked high glucose-induced collagen I upregulation at transcriptional and protein levels. CONCLUSIONS/INTERPRETATION:We conclude that EGFR-PI3K-Akt signalling mediates high glucose-induced collagen I upregulation in mesangial cells and that this pathway is activated in diabetic glomeruli. Targeting its components may provide a new therapeutic approach to diabetic kidney disease.

journal_name

Diabetologia

journal_title

Diabetologia

authors

Wu D,Peng F,Zhang B,Ingram AJ,Gao B,Krepinsky JC

doi

10.1007/s00125-007-0721-1

subject

Has Abstract

pub_date

2007-09-01 00:00:00

pages

2008-2018

issue

eissn

0012-186X

issn

1432-0428

pii

10.1007/s00125-007-0721-1

journal_volume

pub_type

杂志文章

在线工具

Collagen I induction by high glucose levels is mediated by epidermal growth factor receptor and phosphoinositide 3-kinase/Akt signalling in mesangial cells.