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Abstract: PO0680

The Emerging Role of the mTORC2/Rictor Signaling Complex in Autophagy Dysregulation-Associated Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Alkhansa, Sahar, American University of Beirut Faculty of Medicine, Beirut, Lebanon
  • Azar, Sami, American University of Beirut Faculty of Medicine, Beirut, Lebanon
  • Eid, Assaad Antoine, American University of Beirut Faculty of Medicine, Beirut, Lebanon
  • Ziyadeh, Fuad N., American University of Beirut Faculty of Medicine, Beirut, Lebanon
Background

Podocyte injury has been implicated in the pathogenesis of many renal diseases including diabetic kidney disease (DKD). Dysregulation of podocyte autophagy has been positively correlated with podocyte loss and progression of proteinuria in patients with diabetes. Yet, the exact mechanisms behind diabetes-induced autophagy dysregulation remain to be elucidated. Various signaling pathways including the mTORC1 complex have been implicated in maintaining podocyte integrity in DKD. However, the role of mTORC2 in autophagy and its interaction with key mechanistic pathways involved in DKD, including the ROS-producing enzymes, are still unknown. Herein, we investigated the role of mTORC2, its crosstalk with the NADPH oxidases 4 (Nox4)-induced ROS, its effect on autophagy, and the possible link to podocyte integrity in animal models of type 1 and type 2 diabetes.

Methods

Type1 diabetes was induced in mice by streptozotocin (STZ) injections, and type 2 diabetes was initiated by a ‘western’ diet followed by low-dose STZ injections. Mice were divided into control, diabetic, and diabetic treated with a selective mTORC2 inhibitor (JR-AB2-011). Functional, pathological, and biochemical studies were performed.

Results

Diabetes-induced podocyte injury is reflected by alterations of the slit-diaphragm protein nephrin, paralleled by podocyte depletion as assessed by decreased WT1 staining and accompanied by autophagy dysregulation. The effect of autophagy was further highlighted in control mice treated with the autophagy inhibitor hydroxychloroquine, that mirrored the effect of diabetes on functional, phenotypic, histological, and molecular changes in the kidney. These observations were concomitant with an observed activation of the mTORC2/Rictor protein expression and increased levels of superoxide generation through Nox4. Of interest, these results were paralleled by activation of the mTORC1/p70S6K pathway. Moreover, specific inhibition of mTORC2 curbed the homeostatic function of the kidneys and restored the histological and phenotypical changes, concomitant with regulating the Nox4/mTORC1 signaling axis. More importantly, JR treatment regulated diabetes-induced autophagy protein dysregulation (Beclin, Atg3, and LC3).

Conclusion

Our data suggest that targeting mTORC2 signaling could be a potential therapeutic target for DKD.

Funding

  • Private Foundation Support