Substantial evidence suggests that genetic factors predispose patients to diabetic renal disease, which can be exacerbated by poorly managed hyperglycemia. Glucose-derived Advanced Glycation Endproducts (AGE) that accumulate with aging and, at an accelerated rate in vascular and renal tissues in both IDDM and NIDDM subjects have been linked to irreversible renal damage. Recent human studies have revealed a major environmental risk factor that can exacerbate renal disease in DM: dietary AGEs (glycotoxins) that are abundant in foods. A cell-associated AGE-specific receptor (AGE-R) system, present on numerous cells and several glomerular components, including mesangial cells (MC) and endothelium, modulates growth-related mediators and matrix synthesis in vitro. Thus, AGE-R interactions with native and environmental AGEs in vivo may be instrumental in diabetes- and age-related nephropathy. In susceptible individuals, the AGE-receptor expression/function is subject to environment- and/or gene-related alterations, which, together with metabolic/hormonal factors of diabetes, may influence renal cell and matrix gene functions. Preliminary data suggest altered level, and activity of AGE-R in MC from non-obese diabetic (NOD) mice as well as in blood cells of DN-prone IDDM patients. The goals of this proposal are to explore: 1) the in vitro regulation of the glomerulus-specific MC AGE-R by modulators associated with diabetes: glucose, insulin, AGEs, growth factors/cytokines; 2a) to establish the in vivo dysregulation of the glomerular AGE-R expression/function by diabetes, using diabetes-prone animal models susceptible (NOD) or resistant (BB/Wor) to DN, and AGE-infused, non-diabetic animals, 2b) to elucidate in vivo turnover of dietary-AGE and its contribution to AGE-R dysfunction in DN susceptible animals, 3a) to explore the relationship of human DN with the level of expression of AGE-R activity in blood mononuclear cells (PBM) and EBV-transformed lymphoblast cell lines from DM patients wit/without DN, and 3B) to begin exploring whether AGE-R gene mutations/defects contribute to the susceptibility of certain persons to DN. The findings are intended to: provide insights for new therapeutic targets and/or novel methods for early detection of, and intervention with diabetic kidney disease. Since aging-related nephropathy shares significant aspects of AGE toxicity, as well as of diabetes and its complications, the positive outcome of these studies is likely to benefit both rapidly expanding populations, diabetic and nondiabetic adults.
