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Leptin-mediated downregulation of glutathione peroxidase 4 and iron overload contributing to podocyte ferroptosis in diabetic nephropathy

Hangel, Christoph

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Abstract

For almost two decades the dogma of the unifying hypothesis published by Brownlee defines the major research topics in the field of diabetes research. Unfortunately, normalization of blood glucose levels using insulin treatment can postpone or reduce but cannot prevent diabetic late complications. Factors related to obesity may play an important role and are pivotal for the severity and progression of type 2 diabetes. Therefore, this thesis focuses at three characteristics observed during the progression of diabetic nephropathy, i.e. leptin signaling, iron overload and reduction of GPx-4 protein abundance leading to ferroptosis of podocytes. We assume that even though obesity leads to impaired leptin signaling in neurons of the central nervous system, high leptin signaling takes place in peripheral organs like the kidney, contributing to obesity-related disorders. The aim of this study was to show that hyperglycemia itself is not the main reason for developing diabetic nephropathy, but rather an epiphenomenon pivotal to induce a self-reinforcing feedback loop driving the inactivation of GPx-4. The resulting detrimental accumulation of lipid hydroperoxides could trigger the novel programmed cell death pathway ferroptosis in podocytes, which might explain the loss of these cells during the progression of the disease. In the present study we demonstrate that microvascular endothelial cells respond to leptin with an increased release/activation of transforming growth factor (TGF) 1 çausing downregulation of GPx-4 protein in the nearby podocytes. Moreover, a role of leptin signaling and systemic iron overload was analyzed ex vivo by quantifying the amount of GPx-4 protein and iron in the glomeruli of db/db mice, db/db/Fpn+/- mice and leptin-deficient ob/ob mice. GPx-4 protein abundance was slightly reduced in the glomeruli of 32-42 weeks old db/db mice. This decline of GPx-4 protein abundance was augmented in db/db/Fpn+/- mice of the same age. In contrast, the amount of iron was significantly increased in the glomeruli of these mice. Impaired iron homeostasis could influence the activity of GPx-4 in podocytes as we showed that iron accumulates in the glomeruli of Fpn+/- mice. The co-action of both the downregulation of GPx-4 in podocytes induced by leptin signaling in glomerular endothelial cells in combination with the postulated accumulation of iron in the podocytes could thus trigger a negative and self-sustained feedback loop. Obesity is a major risk factor for the development of type 2 diabetes but so far, its relationship with diabetic kidney disease remained unclear. This thesis may have helped to gain insight into one important aspect of the pathogenesis of obesity-related diabetic nephropathy and to facilitate the development of future therapies.

Item Type: Dissertation
Supervisor: Hecker, Prof. Dr. Markus
Place of Publication: Heidelberg
Date of thesis defense: 24 October 2019
Date Deposited: 08 Nov 2019 10:24
Date: 2019
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 000 Generalities, Science
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