BACKGROUND/AIMS: Oxidative stress (OS) contributes to all chronic diabetic complications, including diabetic nephropathy (DN). Acidic fibroblast growth factor (aFGF) has shown to confer protection from OS. However, it also has potent angiogenic activity. We hypothesized that a modified human aFGF (maFGF), with antioxidant properties but devoid of angiogenic activity, has preventative action in DN. METHODS: Streptozotocin-induced diabetic mice were treated with maFGF (intraperitoneally) daily for 1 or 6 months and were compared with untreated diabetic and non-diabetic controls. Microalbuminuria was assessed to determine functional damage. Renal cortical tissues were examined for multiple extracellular matrix proteins, vasoactive factors and OS markers. For mechanistic studies, immortalized mouse podocytes and human microvascular endothelial cells were exposed to high (25 mM) or low glucose (5 mM). OS, vasoactive factors, fibrosis and apoptosis-related gene expression were tested by real-time qPCR and Enzyme-Linked Immunosorbent Assay. Nitric oxide (NO) analyses were also performed. RESULTS: maFGF did not affect body weight and glycemia but prevented renal hypertrophy and functional changes in DN. It also prevented diabetes-induced DNA damage, nitrosative stress, vasoactive factors, angiotensinogen and endothelial NO synthase alterations. Although it failed to prevent transforming growth factor (TGF)-β1 mRNA upregulation, it prevented fibronectin production. Similar results were obtained in vitro. Decreased NO production in vivo and in vitro was also prevented by maFGF. CONCLUSIONS: maFGF treatment prevents DN. This prevention probably involves NO production.
BACKGROUND/AIMS: Oxidative stress (OS) contributes to all chronic diabetic complications, including diabetic nephropathy (DN). Acidic fibroblast growth factor (aFGF) has shown to confer protection from OS. However, it also has potent angiogenic activity. We hypothesized that a modified humanaFGF (maFGF), with antioxidant properties but devoid of angiogenic activity, has preventative action in DN. METHODS:Streptozotocin-induced diabeticmice were treated with maFGF (intraperitoneally) daily for 1 or 6 months and were compared with untreated diabetic and non-diabetic controls. Microalbuminuria was assessed to determine functional damage. Renal cortical tissues were examined for multiple extracellular matrix proteins, vasoactive factors and OS markers. For mechanistic studies, immortalized mouse podocytes and human microvascular endothelial cells were exposed to high (25 mM) or low glucose (5 mM). OS, vasoactive factors, fibrosis and apoptosis-related gene expression were tested by real-time qPCR and Enzyme-Linked Immunosorbent Assay. Nitric oxide (NO) analyses were also performed. RESULTS: maFGF did not affect body weight and glycemia but prevented renal hypertrophy and functional changes in DN. It also prevented diabetes-induced DNA damage, nitrosative stress, vasoactive factors, angiotensinogen and endothelial NO synthase alterations. Although it failed to prevent transforming growth factor (TGF)-β1 mRNA upregulation, it prevented fibronectin production. Similar results were obtained in vitro. Decreased NO production in vivo and in vitro was also prevented by maFGF. CONCLUSIONS: maFGF treatment prevents DN. This prevention probably involves NO production.