The normal aging process is well-known to be associated with a gradual decline in renal function, including a decrease in glomerular filtration rate (GFR). The decrease in GFR is associated with glomerulosclerosis, accumulation of extracellular matrix proteins and proteinuria. Recent studies suggest that the age-related decline in renal function is not necessarily an inevitable consequence of the aging process but that several factors, including angiotensin II, transforming growth factor-beta (TGF-beta), oxidative stress, nitric oxide and advanced glycosylation end products (AGEs) play a role in the age-related renal disease and that inhibition of these processes may retard the progression of renal disease. Our unifying hypothesis is that there are also age-related alteration in renal lipid metabolism that result in accumulation of lipids, including triglycerides and cholesterol in the kidney and that these lipid alterations play an important role in the age-related renal disease by inducing increased expression of growth factors (TGF-beta, AII), pro- inflammatory cytokines and oxidative stress that mediate the accumulation of extracellular matrix proteins and injury to the mesangium and podocytes resulting in glomerulosclerosis, hallmarks of age-related renal disease. The specific objectives for this pilot grant are to determine: 1) if in the aging rat there is alteration in renal lipid metabolism resulting in lipid accumulation, 2) if the recently discovered transcriptional factors including the sterol regulatory element binding proteins (SREBP- and SREBP-2), and oxysterol receptors (LXRalpha and LXRbeta), peroxisome proliferator activated receptors (PPAR-alpha and PPAR- gamma) mediate the alterations in lipid metabolism, and 3) if these lipids induce glomerulosclerosis by inducing growth factors, pro-inflammatory cytokines and oxidative stress.
