475-P: Renal Loss of mTORC2 Is Associated with Improved Diabetic Nephropathy in Type 1 Diabetes

One of the major pathological features of early stage diabetic nephropathy (DN) is tubulointerstitial fibrosis on renal proximal tubular cells (RPTCs), which eventually progresses to fibrosis without proper renal function. However, little is known about the factors regulating these processes. Here, we show that mTOR complex 1 and 2 specifically regulate metabolic control processes of type-1 diabetes in kidney. Using conditional mouse genetic approaches to disable subunits of mTORC1 (Rictor) and mTORC2 (Raptor), respectively or both in PRTCs (Pax8cre), we showed that mice lacking Rictor or Raptor/Rictor develop improved renal pathologies in STZ induced type-1 diabetic model, including low levels of proteinuria, reduced matrix protein accumulation/matrix expansion and tubulointerstitial inflammation. However, the mice lacking Raptor alone were still largely susceptible to STZ toxicity. Meanwhile, Nox4 and oxidative stress levels were significantly reduced in Rictor^cKO diabetic animal, but to a lesser extent in Raptor^cKO diabetic mice. Transcriptome analysis of kidney cortex identified unique pathways that play roles in mTORC/Nox4 pathway during type-1 diabetic pathogenesis, including autophagy, metabolism of lipids and fatty acid regulation. These pathways were largely unchanged in Rictor^cKO mice when they were exposed to STZ induction. Functionally, losing mTORC2 complex resulted in reduced cellular death and oxidative stress levels, and a profound perturbation of the endocytic machinery. Finally, we found that the treatment with pp242, the mTORC1/2 dual inhibitor, greatly ameliorated the renal pathology in OVE26 mice, a spontaneous type-1 diabetic model. Collectively, our findings highlight a novel mTOR-dependent regulatory network for maintaining metabolic homeostasis in RPTCs during the pathogenesis of DN, and further validates the relevance of simultaneously targeting Nox4 and mTORC2 as a potential early therapeutic option for treating DN.