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Abstract: TH-PO185

The Evolving Role of the LXR/mTOR Signaling Axis in Diabetes-Induced Autophagy Alteration and Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Alkhansa, Sahar, American University of Beirut, Beirut, Lebanon
  • Njeim, Rachel, 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

Diabetes is a metabolic disease that induces kidney injury and is considered the most common cause of end-stage kidney disease. It is well recognized that kidney cells depend on basal autophagy for survival and for conserving overall kidney integrity. New lines of research indicate that diabetes induces renal autophagy deregulation leading to kidney injury, yet the underlying mechanisms are not well elucidated. The mTOR complexes along with oxidative stress have emerged as potentially key players in mediating diabetes-induced autophagy imbalance. Alongside, the role of the Liver-X-Receptor (LXR), which is a nuclear receptor, has been also highlighted in diabetic kidney diseases (DKD). Nevertheless, the role of LXR in autophagy and its crosstalk with key mechanistic pathways in DKD remain to be identified. Herein, we investigate the role of the LXR/mTOR/Akt axis in autophagy and its possible link to podocyte injury in type 1 diabetes mellitus (T1DM).

Methods

T1DM was induced in 8-week-old C57BL/6J or FVB/NJ mice by streptozotocin (STZ) injection. Mice were treated with either LXR activator T0, mTORC1 inhibitor Rapamycin, mTORC2 inhibitor JR, or mTORC1/2 inhibitor PP242. Functional, histological, biochemical, and molecular parameters of the kidneys were assessed.

Results

Results show that T1DM induces autophagy deregulation which is accompanied by an increase in both mTORC1 and mTORC2 activity, a decrease in LXR expression, and an increase in the levels of superoxide anion generation through the NADPH oxidase 4 (Nox4) pathway. Inhibition of mTORC2 or mTORC1/2 restores the homeostatic functional renal levels by reducing proteinuria, restoring histological and phenotypical changes to near-normal levels, and inhibiting Nox4 expression. Of interest, these treatments ameliorate diabetes-induced autophagy homeostatic deregulation by restoring the expression of LC3 and p62. Furthermore, activating LXR by T0 corrects the observed changes seen in the mTOR complexes, restores autophagy, and reverses diabetes-induced renal injury.

Conclusion

To our knowledge, this is the first study to provide evidence for a novel function of LXR/mTOR complexes in regulating autophagy in the onset of kidney disease in diabetes.