Abstract: SA-PO438
Targeting the LXR/mTOR Signaling Axis: A Novel Therapeutic Strategy for Modulating Autophagy in Diabetic Kidney Disease
Session Information
- Diabetic Kidney Disease: Basic - II
November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Alkhansa, Sahar, American University of Beirut, Beirut, Lebanon
- Njeim, Rachel, American University of Beirut, Beirut, Lebanon
- Al Moussawi, Sarah, American University of Beirut, Beirut, Lebanon
- Ziyadeh, Fuad N., American University of Beirut, Beirut, Lebanon
- Eid, Assaad Antoine, American University of Beirut, Beirut, Lebanon
Background
Autophagy, vital for maintaining kidney homeostasis, is impaired in podocyte dysfunction and diabetes-induced podocyte injury. However, the underlying mechanisms behind autophagy alteration remain poorly understood. Both mTOR complexes and oxidative stress have been implicated as potential key players in diabetes-related autophagy imbalance, yet the mechanisms leading to their alterations are unclear. Additionally, the role of Liver-X-Receptor (LXR) in autophagy and its interaction with other pathways in diabetic kidney disease (DKD) is not well defined. This study aims to elucidate the role of the LXR/mTOR axis in autophagy and its connection to podocyte injury in type 2 diabetes (T2D)
Methods
In vitro experiments were performed using cultured human podocytes while in vivo experiments were conducted using control mice and T2D mice. T2D mice were treated with different pharmacological drugs to inhibit specific components of the mTOR complex: rapamycin for mTORC1, JR-AB2-011 for mTORC2, and PP242 for mTORC1/mTORC2. Another group of T2D mice was treated with T0 to activate LXR. In parallel, control mice were treated with Hydroxychloroquine (HCQ), an autophagy inhibitor, to further investigate the role of autophagy
Results
High glucose levels or hyperglycemia can lead to podocyte injury and dysregulation of autophagy. This is primarily caused by the production of reactive oxygen species (ROS) through NADPH oxidase activation. Additionally, LXR deactivation and mTORC1/mTORC2 activation contribute to these effects. Activation of LXR using T0 restores renal homeostasis by reducing proteinuria, reversing histological and phenotypical changes, and inhibiting NOX4. Moreover, LXR activation improves diabetes-induced autophagy alteration by restoring the expression of LC3B and p62. LXR activation also reduces the activation of both mTORC1 and mTORC2. Furthermore, inhibiting mTORC1, mTORC2, or mTORC1/2 pathways replicates the effects of LXR activation on ROS production and renal injury, but it does not affect the LXR pathway. Conversely, inhibiting autophagy in control mice using HCQ alone is enough to induce kidney injury
Conclusion
This study presents evidence for a novel role of LXR/mTOR in regulating oxidative stress and autophagy during the onset and progression of diabetic kidney disease (DKD)