title: mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice.
abstract: Diabetic nephropathy (DN) is among the most lethal complications that occur in type 1 and type 2 diabetics. Podocyte dysfunction is postulated to be a critical event associated with proteinuria and glomerulosclerosis in glomerular diseases including DN. However, molecular mechanisms of podocyte dysfunction in the development of DN are not well understood. Here we have shown that activity of mTOR complex 1 (mTORC1), a kinase that senses nutrient availability, was enhanced in the podocytes of diabetic animals. Further, podocyte-specific mTORC1 activation induced by ablation of an upstream negative regulator (PcKOTsc1) recapitulated many DN features, including podocyte loss, glomerular basement membrane thickening, mesangial expansion, and proteinuria in nondiabetic young and adult mice. Abnormal mTORC1 activation caused mislocalization of slit diaphragm proteins and induced an epithelial-mesenchymal transition-like phenotypic switch with enhanced ER stress in podocytes. Conversely, reduction of ER stress with a chemical chaperone significantly protected against both the podocyte phenotypic switch and podocyte loss in PcKOTsc1 mice. Finally, genetic reduction of podocyte-specific mTORC1 in diabetic animals suppressed the development of DN. These results indicate that mTORC1 activation in podocytes is a critical event in inducing DN and suggest that reduction of podocyte mTORC1 activity is a potential therapeutic strategy to prevent DN.
authors: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA. inokik@umich.edu
authors: Ken
authors: K
authors: Inoki
authors: Hiroyuki
authors: H
authors: Mori
authors: Junying
authors: J
authors: Wang
authors: Tsukasa
authors: T
authors: Suzuki
authors: SungKi
authors: S
authors: Hong
authors: Sei
authors: S
authors: Yoshida
authors: Simone M
authors: SM
authors: Blattner
authors: Tsuneo
authors: T
authors: Ikenoue
authors: Markus A
authors: MA
authors: Rüegg
authors: Michael N
authors: MN
authors: Hall
authors: David J
authors: DJ
authors: Kwiatkowski
authors: Maria P
authors: MP
authors: Rastaldi
authors: Tobias B
authors: TB
authors: Huber
authors: Matthias
authors: M
authors: Kretzler
authors: Lawrence B
authors: LB
authors: Holzman
authors: Roger C
authors: RC
authors: Wiggins
authors: Kun-Liang
authors: KL
authors: Guan
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