Mitochondrial-Derived Superoxide in Type 2 Diabetic Kidney Disease

Va San Diego Healthcare System, San Diego CA

Investigators

Linked publications & trials

Abstract

? DESCRIPTION (provided by applicant): Each year in the United States, more than 100,000 people are diagnosed with kidney failure. Diabetes is the most common cause of chronic kidney disease and kidney failure. From the last several years, our research efforts are focused on identifying molecular mechanisms and potential biomarkers involved in the complications of diabetic kidney disease. Our research established a central role for the pro-fibrotic cytokine Transforming Growth Factor- (TGF) in diabetic nephropathy. We also showed that the hormone adiponectin negatively correlates with albuminuria in obese African Americans, a portion of the VA population that has a high incidence of kidney disease. This observation directly led us to the recognition that the master energy sensor, the enzyme AMP activated protein kinase (AMPK), is regulated by adiponectin and plays a major role in kidney disease. Our recent studies, supported by VA Merit funding, further demonstrated that both type 1 diabetic kidney disease and obesity-related kidney disease are characterized by reduced AMPK activity. Restoration of AMPK activity blocked matrix accumulation and TGF- production and activity. In addition, we recently found that AMPK activation reduces inflammation and hydrogen peroxide levels, likely via regulation of NAPDH oxidase. By using GC-MS based metabolomic analysis we recently identified a significant reduction in 13 metabolites, potential biomarkers of kidney function, in patients with diabetes and chronic kidney disease. Twelve of the 13 differentially expressed metabolites are linked to mitochondrial metabolism, suggesting defective mitochondrial activity. Another major recent breakthrough was that by using novel real-time imaging techniques, we found that mitochondrial superoxides are reduced in the kidneys and heart of animal models with type 1 diabetes, which is in contrast to the current belief that increased mitochondrial superoxide is responsible for organ damage. Stimulation with AMPK activators resulted in an increase in mitochondrial content, an increase in mitochondrial complex activity, an increase in mitochondrial superoxide production and resolution of inflammation and fibrosis. Therefore, we hypothesize that alterations in substrate oxidation and mitochondrial activity may play a key role in early diabetic kidney disease and prolonged reduction of mitochondrial content may lead to organ failure. However, similar studies have not been performed in type 2 diabetes. Although we find evidence of reduced mitochondrial function in patients with type 2 diabetes and CKD, we have not established the basis of these findings using animal models. As type 2 diabetes development is very different than pathogenesis of type 1 diabetes, there could be different effects on metabolism and mitochondrial function. However, in preliminary studies we find that mitochondrial superoxide is also reduced in the kidney of the db/db mouse model of type 2 diabetes. The current proposal will be focused to understand the mechanisms and consequences of mitochondrial derived superoxides in type 2 models of diabetic kidney disease. We will analyze specific changes associated with mitochondrial and cellular metabolism and approaches to improve mitochondrial function with the aim of identifying targets for therapeutic intervention.