Doctor of Philosophy (PHD)
Molecular and Cellular Pharmacology (Medicine)
Date of Defense
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Abnormalities in lipid metabolism can be observed in patients at all stages of chronic kidney disease (CKD). Most commonly, dyslipidemia is due to defects in cholesterol or sphingolipid metabolism. However, the exact mechanisms by which dyslipidemia contributes to or causes glomerular disease have not been well defined. To elucidate the role of dyslipidemia in podocytes, which are cells with an important role in glomerular function, we focused our interest on studying the mechanisms by which altered cholesterol and sphingolipid metabolism contributes to podocyte injury. As inflammation is highly prevalent in patients with CKD and inflammation was shown to contribute to changes in lipid metabolism, we aimed to establish a link between two inflammatory markers, soluble urokinase activator receptor (suPAR) and tumor necrosis factor alpha (TNF), dyslipidemia and podocyte injury in two glomerular diseases, diabetic kidney disease (DKD) and focal segmental glomerulosclerosis (FSGS). In our first study, we identified an important role for podocyte TNF in free cholesterol mediated podocyte apoptosis in DKD and FSGS. We showed that increased local TNF caused free cholesterol mediated podocyte apoptosisrequiring both, decreased nuclear factor of activated T-cells (NFAT) mediated ATP-binding cassette A1 (ABCA1) expression and reduced sterol-O-acyl transferase (SOAT1) cholesterol esterification. This study uncovers a novel mechanism by which circulating TNF or other circulating factors that increase local TNF expression in podocytes contribute to podocyte injury. In our second study, we describe an important role for acid sphingomyelinase acid like 3b (SMPDL3b) in the pathogenesis of DKD and in FSGS. We demonstrate that the inflammation associated marker, soluble urokinase activator receptor (suPAR) is elevated in the sera from patients with FSGS and DKD whereas SMPDL3b is differentially expressed and expression was found to be increased in podocytes in DKD but decreased in FSGS. Mechanistically, we show that differential SMPDL3b expression alters suPAR mediated signaling causing either a migratory phenotype in the case of reduced or apoptosis in the case of elevated SMPDL3b expression. Taken together, our data identify novel pathways that contribute to the pathogenesis of DKD and FSGS and this study may therefore help identify new targets for the development of pharmaceutical agents to treat podocyte injury in FSGS and DKD.
Podocyte; Lipid; Apoptosis; Kidney Disease; Cholesterol; Sphingolipid
Pedigo, Christopher E., "The Role of Cholesterol and Sphingolipids in Glomerular Disease" (2016). Open Access Dissertations. 1667.
Available for download on Thursday, May 17, 2018