The pathogenic role of certain toxic oxygen metabolites has become an important focus of research in nephrology in recent years. This interest was triggered by the observation that exogenous antioxidants ameliorates various types of renal injury. Similar to other organ systems, the kidneys are equipped with efficient antioxidant systems including, antioxidant enzymes (AOEs) which intercept the initial products of partially reduced oxygen molecules. In the last few years, the PI showed that endogenous AOEs such as manganese superoxide dismutase (Mn-SOD), are crucial in moderating the extent of damage in several forms of glomerular injury. The proposed projects will address some important unanswered questions in the management of nephrotic syndrome, namely: why glomerular injury in very young children carries a particularly poor prognosis; why some minimal change disease progress to focal segmental glomerulosclerosis. The experimental protocols described in the project are designed to test the possibility that the maturation status of AOE system is a crucial determinant in these clinical observations. Despite the extensive use of glucocorticoids in treatment of nephrotic syndrome, the mechanisms for their actions remain unclear. The PI has shown that glucocorticoids enhance both glomerular Mn-SOD activity and gene expression. The co-investigators have cloned 5'-flanking region (i.e., the regulatory region of the gene) of Mn-SOD genomic DNA, allowing in depth exploration of the regulatory mechanisms of Mn-SOD gene transcription. An important focus of these projects is the study of mechanisms of this Mn-SOD gene regulation by glucocorticoids and verification of its functional significance. Overall, using state-of-the-art molecular biological techniques, functional enzyme assays and parameters of glomerular function, and structure, these projects attempt to obtain new insights into the biology of renal antioxidant enzyme systems in nephrotic syndrome.
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