Abstract: FR-PO396
LXR/mTOR/Nox4 Signaling Axes: Novel Therapeutic Targets in Diabetic Nephropathy
Session Information
- Diabetic Kidney Disease: Basic - II
October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Alkhansa, Sahar, American University of Beirut, Beirut, Lebanon
- Eid, Stephanie Atef, American University of Beirut, Beirut, Lebanon
- El mouhayyar, Christopher, American Univeristy of Beirut , Naccache, Lebanon
- Mahjoub, Neamah, American University of Beirut, Beirut, Lebanon
- Barakat, Rasha, Universite Paris Descartes, Amioun, Lebanon
- Eid, Assaad Antoine, American University of Beirut/Faculty of Medicine, Beirut, Lebanon
Background
Podocyte injury has emerged as a key mediator in the initiation of Diabetic Nephropathy (DN). The molecular mechanism by which hyperglycemia induces podocyte injury is multi-factorial and not well defined. Recent studies have described the potentiality of defective autophagy mechanisms on the onset and development of diabetes. Our lab has described the importance of renal NADPH Oxidases (Noxs) in the progression of podocyte injury. Yet, a mechanistic pathway between Nox-induced ROS production and the alteration in autophagy has yet to be clarified. Liver-X-receptor (LXR) and the mTOR pathway have recently been linked to autophagy and oxidative stress. In this study we aim to assess the role of Nox/LXR/mTOR axes on autophagy and their possible links to podocyte depletion and injury.
Methods
Pharmacological means were utilized to alter the expression of Noxs, LXR and the mTOR signaling pathways, while podocyte depletion/loss, autophagy alteration and glomerular injury were assessed as the corresponding biological output both in vitro and in vivo.
Results
Our results reveal that high glucose (HG) induces defective autophagy in both podocytes and isolated glomeruli of type 2 diabetic mice. HG reduces LXR mRNA levels and protein expression and activates the mTORC1/p70S6kinase pathway. HG also increases the levels of Nox4 and Nox activity and induces ROS production. Activation of the LXR pathway using an LXR activator T0, decreases HG-induced Nox4 expression, Nox activity, inactivates the mTORC1 pathway, and restores autophagy protein levels. In parallel, inactivation of the mTORC1 pathway using low dose rapamycin, mimicked the effect of T0 on ROS production and podocytes injury but did not alter the LXR pathway, suggesting that mTORC1 is downstream of LXR and Noxs are the final common pathway altered in our experimental model. More importantly, our results display the role of Nox4 in autophagy, where inactivation of Nox4, using GKT, a potent Nox1 and Nox4 inhibitor, restores homeostatic autophagy levels, and reduces podocytes and glomerular injury.
Conclusion
Thus, LXR activation, mTOR and/or NADPH oxidase inhibition may represent a therapeutic modality for diabetic kidney disease.