Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Pathology

Supervisor

Dr. Subrata Chakrabarti

Abstract

Oxidative stress is a key mechanism causing Diabetic Nephropathy (DN). Acidic fibroblast growth factor (aFGF) is known to confer protection from oxidative stress. However, it also has significant angiogenic activity. Hence, we have generated a mutated human acidic FGF (maFGF), with intact antioxidant properties but devoid of angiogenic activities. Recent evidence shows that maFGF treatment prevented diabetic cardiomyopathy and further in vitro studies suggest that this prevention is mediated by suppression of cardiac oxidative stress, hypertrophy and fibrosis. We hypothesized that maFGF treatment has a protective effect in DN.

We show that maFGF treatment did not affect body weight and blood sugar levels in a type 1 diabetic mouse model. However maFGF prevented renal functional alterations in diabetes and decreased renal hypertrophy following long-term diabetes. maFGF also prevented diabetes–induced DNA damage, upregulation of angiotensinogen, oxidative stress marker heme oxygenase 1, and alteration of endothelial nitric oxide synthase (eNOS). Surprisingly, it failed to prevent upregulation of the fibrogenic cytokine transforming growth factor β1 mRNA expression. However, long term administration of maFGF partially prevented diabetes-induced extracellular matrix proteins accumulation. Further analyses showed similar results in high glucose-induced alterations in podocytes and microvascular endothelial cells. Likewise, maFGF showed prevention of diabetes- induced decreased nitric oxide (NO) production and apoptosis in vivo and in vitro. These results were consistent with the prevention of long term diabetes- induced down regulation of eNOS enzyme. Data from these experiments suggest that the preventative effects of maFGF treatment in DN are probably via alteration of NO production, and indicate a potential therapeutic role of maFGF in DN.

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