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J. Biol. Chem., Vol. 278, Issue 41, 39349-39355, October 10, 2003

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Phosphatidylinositol 3'-Kinase-dependent Activation of Renal Mesangial Cell Ki-Ras and ERK by Advanced Glycation End Products^*

Dazhong Xu and John M. Kyriakis 

From the Molecular Cardiology Research Institute, New England Medical Center and the Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts 02111

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-, 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-. 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.

Received for publication, March 18, 2003 , and in revised form, June 24, 2003.

^* This work was supported by United States Public Health Service Grants R01-DK41513 (to J. M. K.) and F32-DK62680 (to D. X.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Molecular Cardiology Research Institute, New England Medical Center, 750 Washington St., Box 8486, Boston, MA 02111. Tel.: 617-636-5190; Fax: 617-636-5204; E-mail: jkyriakis{at}tufts-nemc.org.

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