All ETDs from UAB

Advisory Committee Chair

Victor Darley-Usmar

Advisory Committee Members

Rakesh Patel

Jack Lancaster

Anupam Agarwal

Joanne Murphy-Ullrich

John Chatham

Document Type

Dissertation

Date of Award

2012

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

TARGETING MITOCHONDRIAL FUNCTION IN DIABETIC NEPHROPATHY The incidence of diabetes has increased to epidemic proportions over the last 50 years, due to a complex interaction of lifestyle and dietary factors. Changes in physical activity, caloric intake, and the composition of foods consumed over the last century are thought to interact with metabolic syndrome prone subpopulations leading ultimately to diabetes. It is widely accepted that chronic hyperglycemia in the blood characterizes the diabetic condition. Since the discovery of insulin therapy in the first half of the 20th century, diabetics have extended their lifespan considerably, but at the cost of increased morbitity from complications such as nephropathy, neuropathy, and retinopathy. Large scale studies assessing the long term effects of variations in blood glucose levels in diabetic patients have associated increased blood sugar levels with higher rates of secondary complications. The current paradigm for diabetic treatment centers on controlling blood glucose levels, and as such, a number of drugs have been developed targeting insulin levels and action. While current therapies are beneficial in reducing long term complications, significant limitations exist. This includes the need for intensive therapy early in disease progression, decreased efficacy over time, and reliance on patients to properly medicate in response to daily glucose fluctuations. A significant amount of research has been undertaken to address the mechanisms by which high glucose levels in diabetics cause organ damage, particularly the kidney which is the focus of investigation in this thesis. An early event in the pathology of diabetes is mitochondrial dysfunction with hyperglycemia induced cell damage. Mitochondria serve a number of functions in the cell, including metabolizing glucose for the generation of energy and producing reactive oxygen species for intracellular signaling. These functions have been found to be critical in mediating hyperglycemic-dependent damage, but also provide a novel target for diabetic therapy. In this thesis, we show that a new class of mitochondrial targeted antioxidants can prevent diabetes induced renal dysfunction. The mechanism of action for these targeted antioxidants in a diabetic context involves controlling the cell signaling pathways leading to fibrosis.

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