Doctor of Philosophy (PHD)
Molecular and Cellular Pharmacology (Medicine)
Date of Defense
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Fibroblasts from patients with Tangier disease carrying ATP-binding cassette A1 (ABCA1) loss of function mutations are characterized by cardiolipin accumulation, a mitochondrial specific phospholipid. Suppression of ABCA1 expression occurs in glomeruli from patients with diabetic kidney disease (DKD) and in human podocytes exposed to DKD sera collected prior to the development of DKD. Furthermore, lipid metabolism dyregulation and lipid accumulation are observed in patients with DKD. However, the exact mechanisms as to how ABCA1 reduction contributes to alterations in mitochondrial lipids and function remains to be established. Therefore, the purpose of this study was to elucidate the mechanistic role reduced ABCA1 plays in contributing to, mitochondrial dysfunction observed in DKD and to podocyte injury in DKD progression. We demonstrated that siRNA ABCA1 knockdown in podocytes leads to reduced oxygen consumption capabilities associated with alterations in the oxidative phosphorylation (OXPHOS) complexes and with cardiolipin accumulation. Podocyte-specific deletion of Abca1 (Abca1 KO) render mice susceptible to DKD, and pharmacological induction of ABCA1 reduced the amount of oxidized cardiolipin and improved established DKD. This was not mediated by free cholesterol, as genetic deletion of sterol-o-acyltransferase-1 (SOAT1) in Abca1 KO mice was sufficient to cause free cholesterol accumulation but did not cause glomerular injury. Instead, cardiolipin mediates ABCA1 dependent susceptibility to podocyte injury, as inhibition of cardiolipin peroxidation with elamipretide improved DKD in vivo and prevented ABCA1-dependent podocyte injury in vitro and in vivo. Collectively, we describe a novel pathway definitively linking ABCA1 deficiency to cardiolipin-driven mitochondrial dysfunction. We demonstrate that this pathway is relevant to DKD and that ABCA1 inducers or inhibitors of cardiolipin peroxidation may each represent novel therapeutic strategies for the treatment of established DKD.
Diabetic kidney disease; lipid metabolism; mitochondrial dysfunction; podocyte injury; lipid peroxidation; oxidative phosphorylation
Ducasa, Gloria Michelle, "The Role of ATP-Binding Cassette A1 as a Susceptibility Factor in Diabetic Kidney Disease" (2019). Open Access Dissertations. 2317.
Available for download on Thursday, June 25, 2020