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Abstract: FR-PO196

Mesenchymal Stem Cells Attenuate Diabetic Kidney Disease by Inhibiting the mTOR Signaling Pathway

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Njeim, Rachel, American University of Beirut, Beirut, Lebanon
  • Youssef, Natalie, American University of Beirut, Beirut, Lebanon
  • Azar, William, American University of Beirut, Beirut, Lebanon
  • Azar, Sami, American University of Beirut Medical Center, Beirut, Lebanon
  • Ziyadeh, Fuad N., AUB, New York, New York, United States
  • Eid, Assaad Antoine, American University of Beirut/Faculty of Medicine, Beirut, Lebanon
Background

Diabetic kidney disease is one of the most serious complications of diabetes worldwide. The earliest clinical manifestation of DKD is increased albuminuria, which eventually progresses to overt proteinuria. Glomerular injury is characterized by hypertrophy, mesangial matrix expansion, basement membrane thickening, and podocyte loss. Emerging body of evidence has revealed that mesenchymal stem cells treatment induces glomerular repair either through differentiation or by acting in a paracrine manner. However, the mechanistic pathway has not yet been identified. We and others have previously shown that in the glomeruli of diabetic animals, the mTORC1/p70 S6Kinase and Rictor/mTORC2 pathways are activated, promoting podocyte injury. In addition, we demonstrated that mTORC1 and mTORC2 inhibition attenuates HG-induced NADPH oxidase activity and decreases Nox1 and Nox4 expression. The present study aims to assess the reno-protective role of MSCs and to investigate the mechanistic pathway by which MSCs exert this protective role.

Methods

Sprague-Dawley rats were divided into the following groups: a control group and a streptozotocin-induced type 1 diabetic group each treated with medium, MSCs-derived medium, or 1x106MSCs. After eight weeks of treatment from diabetes onset, functional, histological, biochemical, and molecular parameters of the kidneys were assessed.

Results

MSCs treatment restored normal urinary albumin excretion levels. Protection against DKD imparted by MSCs was denoted by decreased glomerulosclerosis. Moreover, MSCs treatment restored podocyte foot process effacement and glomerular basement membrane thickening and reversed podocyte depletion. More importantly, and for the first time, we show that MSCs treatment restored the mTORC1/mTORC2 complex integrity. This was paralleled by a decrease in NADPH oxidases activity and NOX4 protein expression. All of these observations were mirrored when diabetic rats were treated with MSCs-derived medium.

Conclusion

Our results suggest that MSCs have a potential therapeutic effect in the treatment of DKD by attenuating mTOR signaling pathway. Furthermore, and to our knowledge, this is the first study to report that MSCs-derived medium mimics the beneficial effect of MSCs suggesting that the trophic factors secreted by the MSCs exert the observed reno-protective effect.

Funding

  • Private Foundation Support