Diabetes has become the leading cause for end stage renal disease in the United States. Emerging evidence indicates that hyperglycemia-induced generation of superoxide within the mitochondria plays a major role in the development of various diabetic complications. However, the precise mechanism(s) responsible for superoxide generation in renal mitochondria and the downstream targets that contribute to the development of mitochondrial dysfunction and renal injury during diabetes remain unclear. Manganese superoxide dismutase (MnSOD) is the primary antioxidant that scavenges superoxide formed within the mitochondria and protects against oxidative stress. In principle, mitochondria could generate superoxide following damage to the mitochondrial respiratory complexes or due to inactivation of MnSOD. Hence, we hypothesize that hyperglycemia leads to damage to mitochondrial complexes and MnSOD inactivation, which increases mitochondrial superoxide leading to mitochondrial dysfunction and renal injury. In this study, we investigated the mechanisms that trigger oxidant production and its potential targets for disruption and damage in the renal mitochondria during hyperglycemia using a STZ-diabetic rat model (in vivo). Furthermore, we tested the protective effects that overexpression of MnSOD has against hyperglycemia induced renal injury using cultured renal proximal tubular cells exposed to hyperglycemia (in vitro). Our findings from these studies indicate for the first time that Complex-III is an early target for diabetes-induced inactivation within the renal mitochondria (both in vivo and in vitro), and thus could play a critical role in the development of mitochondrial dysfunction in the kidney during diabetes. Our studies also conclude that the status of renal MnSOD remains unaltered during hyperglycemia. Most importantly, our in vitro studies indicate that mitochondrial superoxide generation and mitochondrial hyperpolarization precedes the development of mitochondrial dysfunction (Complex-III inactivation and decline in ATP), and renal cell death during hyperglycemia. Remarkably, these hyperglycemia induced changes were completely prevented by overexpression of MnSOD in renal cells. Together, our studies strongly implicate the central involvement of mitochondrial superoxide in the development of mitochondrial dysfunction, and the protective role of MnSOD against diabetes-induced renal injury. Thus, therapeutic approaches to diminish mitochondrial superoxide generation (via mitochondrial targeted antioxidant therapy) during diabetes could hinder the development of nephropathy in diabetic patients.
|Advisor:||Crow, Lee Ann MacMillan|
|School:||University of Arkansas for Medical Sciences|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 69/12, Dissertation Abstracts International|
|Subjects:||Pharmacology, Pathology, Physiology|
|Keywords:||Diabetes, Hyperglycemia, Kidneys, Mitochondrial dysfunction, Nephropathy, Oxidants, Oxidative stress|
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