Phosphatidylinositol 3'-kinase-dependent activation of renal mesangial cell Ki-Ras and ERK by advanced glycation end products.
Advanced glycation end products (AGEs) are produced by the non-enzymatic glycation of proteins and lipids. AGE levels are pathologically elevated in a number of inflammatory diseases and in diabetes mellitus. There is evidence that AGEs, acting through the receptor for AGEs, contribute to diabetic complications. Nephropathy is a major complication of diabetes mellitus. However, the initiating molecular events that trigger diabetic renal disease are unknown. Renal mesangial cells produce excess extracellular matrix in response to treatment with transforming growth factor-beta, and excess mesangial cell matrix production, by impairing glomerular filtration, contributes to diabetic nephropathy. AGEs are known to trigger the autocrine production and release of transforming growth factor-beta. However, it is unclear how AGEs signal in mesangial cells. Here we show that treatment of mesangial cells with AGEs and with the receptor for AGEs agonist S100 triggers activation of the extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3'-kinase (PI3K) pathways. AGEs trigger the GTP loading of mesangial cell Ras, and AGE activation of ERK requires Ras. We observe that Ki-Ras, but not Ha-Ras, is the target of AGE action. Surprisingly, inhibition of PI3K blocks both ERK and Ki-Ras activation. We also observe that activation of ERK and the PI3K target kinase protein kinase-B is blocked with free radical scavengers, indicating a role for reactive oxygen species in AGE recruitment of PI3K. Thus, AGEs signal to Ki-Ras and ERK through reactive oxygen species-dependent activation of PI3K.
Xu
Dazhong
D
Molecular Cardiology Research Institute, New England Medical Center and the Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Kyriakis
John M
JM
D000818:Animals; D003928:Diabetic Nephropathies / Q000209:etiology / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000187:drug effects / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism*
D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017382:Reactive Oxygen Species; D018631:ras Proteins