Protective Effects Ofα-Lipoic Acid against Renal Fibrosis in Diabetic Mice

Advanced glycosylation end products (AGEs) play important roles in the progression of diabetic nephropathy, which lead to renal fibrosis and end stage renal diseases. Suppression of collagen-producing myofibroblast, inhibition of epithelial-mesenchymal transition (EMT) and resorption of fibrous scar have all been shown to be effective in the regression of tissue fibrosis. In the present proposal, we propose to investigate the mechanisms by which N-carboxylmethyl lysine (CML) causes the fibrogenic effects in renal cells. We will explore whetherα-lipoic acid exerts beneficial effects on CML-induced fibrogenic effects. Effcts ofα-lipoic acid on the progression of diabetic nephropathy and renal fibrosis will be investigated in diabetic mice and unilateral ureteral obstruction mice models. Our specific aims are: Specific aim (I): To determine whether treatment of renal tubular NRK49F fibroblatsts or renal epithelial NRK52E or HK-1 cells with CML would (1) activates interstitial fibroblasts, (2) stimulates epithelial-mesenchymal transition (EMT) (3) alters lipid and energy metabolism, and (4) increases extracellular matrix secretion. We will also demonstrate that HIF-1 or osteopontin regulates these effects. Specific Aim (II): To investigate whether α -lipoic acid regulates HIF-1 and osteopontin, which subsequently attenuates the CML- induced fibrogenic effects in renal tubular interstitial cells and renal epithelial cells. Specific Aim (III): To examine effects of α-lipoic acid on the progression of diabetic nephropathy in streptozocin/nicotinamide induced diabetic mice, and the prevention of fibrogenic effects in unilateral ureter obstruction (UUO) mice. The biochemical profile would be compared between control and α-lipoic acid-treated mice The expression levels of osteopontin and HIF-1 will be correlated with the expression level of E-cadherin、vimentin, α-smooth muscle actin (α-SMA), fibroblasts specific protein-1 (FSP-1) and lysyl oxidase in these mice.