Nephropathy is one of the major complications of both type 1 and type 2 diabetes mellitus. Thus approximately 40% of individuals with diabetes will develop kidney disease, and renal failure accounts for a significant proportion of the mortality attributable to diabetes. The progression to diabetic kidney disease is a complex and poorly understood process. Elevated plasma glucose triggers the secretion of transforming growth factor-beta (TGF-Beta) which, in turn, stimulates the pathologically excessive deposition of extracellular matrix-a process mediated by glomerular mesangial cells. Elevated blood glucose also stimulates mesangial cell hyperplasia and hypertrophy. These processes eventually culminate in renal failure. While a direct signaling role for glucose has been proposed, glucose itself is a weak mesangial cell agonist. Advanced glycation endproducts (AGEs), formed by the nonenzymatic glycation of proteins and lipids, are present in excess in diabetes and are thought to be important early in the development of diabetic renal disease. AGEs exert their effects by interacting with the receptor for advanced glycation endproducts (RAGE). RAGE expression is elevated in diabetes. Blockade of RAGE has been shown to suppress vascular hyperpermeabiity and accelerated atherosclerosis in diabetic rats. These results, suggest that AGEs/RAGE play a central role in triggering the early pathophysiologic changes associated with diabetic nephropathy. Accordingly, investigating RAGE intracellular signaling mechanisms and cellular effects is important to furthering our understanding of diabetic renal disease. We propose two broad areas of study: dissection of the signaling pathways coupling mesangial cell RAGE to ERK and PI-3-kinase and identification of signaling elements recruited by RAGE that are important to pathophysiologic changes of mesangial cells associated with diabetes.
| Xu, Dazhong; Patten, Richard D; Force, Thomas et al. (2006) Gene 33/RALT is induced by hypoxia in cardiomyocytes, where it promotes cell death by suppressing phosphatidylinositol 3-kinase and extracellular signal-regulated kinase survival signaling. Mol Cell Biol 26:5043-54 |
| Xu, Dazhong; Makkinje, Anthony; Kyriakis, John M (2005) Gene 33 is an endogenous inhibitor of epidermal growth factor (EGF) receptor signaling and mediates dexamethasone-induced suppression of EGF function. J Biol Chem 280:2924-33 |
| Xu, Dazhong; Kyriakis, John M (2003) Phosphatidylinositol 3'-kinase-dependent activation of renal mesangial cell Ki-Ras and ERK by advanced glycation end products. J Biol Chem 278:39349-55 |
