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Reactive lipids in podocyte homeostasis
Early podocyte loss is characteristic of chronic kidney diseases, edpecially in diabetes and metabolic syndrome related nephropathies. Changes in the redox environment and redox imbalance have been implicated to play a role in podocyte loss, but the mechanisms are not well known. Reactive lipids and their end-products are an established biomarker in human diabetes, but it is not known how reactive lipids may influence podocyte homeostasis. The goal of our proposal is to understand the role of these reactive lipids in modulating podocyte survival signaling. The long term aim is to establish a role for these reactive species in the development of chronic kidney disesase and nephropathy. We have compelling preliminary data to propose that lipid radicals may fine tune podocyte response on an adaptive to maladaptive scale. While low levels of reactive lipids activate prosurvival mechanisms, higher levels may lead to pathology. The mechanisms involve redox sensitive control of rhoA to regulate podocyte motility and cytoskeletal rearrangements, and triggers to the slit diaphragm proteins - Akt axis to modulate survival signaling. To test this hypothesis, we will use in vitro and in vivo experiments, combined with our state of the art free radical approaches. In Aim 1, we will determine that reactive lipids serve as redox instigators of rhoA and survival mechanisms through Akt and podocyte specific proteins. In Aim 2, we will establish that specific scavenging of excess lipid radicals restores adaptive redox signaling in podocytes in vivo. Collectively, these aims will answer an important question - how lipid radicals may trigger podocyte survival or death and therefore how they contribute to podocyte defects and albuminuria. Outcomes from this proposal will advance the field by offering new avenues to targeted, redox based therapies, through understanding the mechanisms modulated by reactive lipids in podocytes.

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