Translational Aspects of the Mammalian Target of Rapamycin Complexes in Diabetic Nephropathy.

Significance: Despite the many efforts put into understanding diabetic nephropathy (DN), direct treatments for DN have yet to be discovered. Understanding the mechanisms behind DN is an essential step in the development of novel therapeutic regimens. The mammalian target of rapamycin (mTOR) pathway has emerged as an important candidate in the quest for drug discovery because of its role in regulating growth, proliferation, as well as protein and lipid metabolism. Recent Advances: Kidney cells have been found to rely on basal autophagy for survival and for conserving kidney integrity. Recent studies have shown that diabetes induces renal autophagy deregulation, leading to kidney injury. Hyper-activation of the mTOR pathway and oxidative stress have been suggested to play a role in diabetes-induced autophagy imbalance. Critical Issues: A detailed understanding of the role of mTOR signaling in diabetes-associated complications is of major importance in the search for a cure. In this review, we provide evidence that mTOR is heavily implicated in diabetes-induced kidney injury. We suggest possible mechanisms through which mTOR exerts its negative effects by increasing insulin resistance, upregulating oxidative stress, and inhibiting autophagy. Future Directions: Both increased oxidative stress and autophagy deregulation are deeply embedded in DN. However, the mechanisms controlling oxidative stress and autophagy are not well understood. Although Akt/mTOR signaling seems to play an important role in oxidative stress and autophagy, further investigation is required to uncover the details of this signaling pathway. Antioxid. Redox Signal. 37, 802-819.