The role of specific Nox isoforms in diabetic renal disease and atherosclerosis

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Diabetes is increasing worldwide and in Australia. The majority of patients with diabetes eventually will develop kidney disease and will die of blood vessel complications such as heart attacks and stroke. Oxidative stress (the generation of free oxygen radicals that react quickly with other proteins in the body causing tissue damage) has been suggested to play an important role in kidney and blood vessel disease observed in diabetic patients. This proposal will try to identify and measure specific proteins in the kidney and vessels that are involved in the production of oxidative stress. We aim to define which one of these proteins is the most important. We will assess in detail how these proteins work and which other factors are activated leading to tissue damage. The ultimate goal of these studies is to find new treatment options to decrease the production of harmful molecules in the kidney and blood vessel wall thereby reducing kidney failure, heart attacks, stroke and gangrene in diabetes. In our studies, we will use medications already used in patients to treat high blood pressure in diabetes. In preliminary studies we have shown that these drugs also reduce oxidative stress. Furthermore, we will use novel, more specific treatments that the harmful ptoteins. Through a collaboration with Professor Harald Schmidt and his group from Germany who have recently moved to Monash University in Melbourne we will have access to mice in which specific genes for harmful proteins have been knocked out. These mice when made diabetic will most likely develop less or no kidney and blood vessel damage. Our studies will help to identify the most important oxidative stress producing protein associated with kidney and vessel disease. This knowledge will lead to more effective and more potent treatments for patients with diabetes to prevent, stop or even improve kidney and blood vessel disease thereby reducing disability and death in this high risk group of patients.