Diabetic nephropathy (DN) is among the most lethal complications that occur in patients with both type 1 and type 2 diabetes. It is characterized as a major glomerulopathy that develops to glomerulosclerosis, leading ultimately to end-stage renal disease (ESRD). Despite considerable attention from both clinicians and basic scientists, the prevalence of ESRD in diabetic patients is increasing dramatically. Thus, understanding the pathogenesis of DN is crucial to developing new approaches for its prevention and treatment. Recent investigations have revealed that injuries to podocytes play a critical role in the development of diabetic nephropathy. These highly differentiated glomerular epithelial cells and their foot processes comprise the slit diaphragm, a barrier for repelling serum proteins on the surface of glomerular capillaries. Podocyte injury may produce micro-albuminuria, an early feature of DN. The molecular mechanisms by which diabetes causes podocyte injury remain unclear. Furthermore, whether podocyte injury is a cause or a consequence of DN also continues to be uncertain. The TSC-mTORC1 pathway is an evolutionarily conserved signaling pathway that regulates growth and survival. This pathway responds to nutrients such as glucose and growth factors, and in turn controls a wide array of cellular processes such as translation, transcription, and autophagy. We have shown that activation of the mTORC1 pathway plays a critical role in diabetes-dependent podocyte injury. Our studies indicate that all pathological alterations present in a mouse model of DN, including podocyte morphological changes, glomerular basement membrane (GBM) thickening, proteinuria, glomerular hypertrophy, and mesangial expansion, can be prevented by treatment with rapamycin, a specific mTOR inhibitor. Moreover, podocyte-specific mTORC1 activation in a non-diabetic mouse recapitulated podocyte injury and other features of DN in a rapamycin-sensitive manner. These observations indicate a critical role for the site-specific activation of mTORC1 in podocytes during the development of DN. To explore this possibility in greater detail, I will focus on understanding how the TSC-mTORC1 pathway is regulated in podocytes during diabetes;the molecular mechanisms underlying mTORC1-dependent podocyte injury;and whether activation of mTORC1 in podocytes is sufficient to produce DN. I anticipate that these studies will reveal much about the molecular mechanisms underlying podocyte injury in DN, and provide important clues for developing new approaches to the treatment of this debilitating disease.

Public Health Relevance

Recent investigations have revealed that injuries to podocytes play a critical role in the development of diabetic nephropathy (DN). The goal of this proposal is to elucidate the role of mTOR pathway as a molecular mechanism underlying podocyte injury in DN. Completion of this project will not only reveal a novel molecular mechanism for podocyte injury but also set the stage for additional studies to explore new therapeutic approaches to the treatment of DN.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK083491-04
Application #
8327837
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Rys-Sikora, Krystyna E
Project Start
2009-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$314,116
Indirect Cost
$100,944
Name
University of Michigan Ann Arbor
Department
Physiology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Hong, Sungki; Zhao, Bin; Lombard, David B et al. (2014) Cross-talk between sirtuin and mammalian target of rapamycin complex 1 (mTORC1) signaling in the regulation of S6 kinase 1 (S6K1) phosphorylation. J Biol Chem 289:13132-41
Inoki, Ken (2014) mTOR signaling in autophagy regulation in the kidney. Semin Nephrol 34:2-8
Tang, Huibin; Inoki, Ken; Lee, Myung et al. (2014) mTORC1 promotes denervation-induced muscle atrophy through a mechanism involving the activation of FoxO and E3 ubiquitin ligases. Sci Signal 7:ra18
Inoki, Ken (2013) Proximal tubules forget "self-eating" when they meet Western meals. J Am Soc Nephrol 24:1711-3
Suzuki, Tsukasa; Bridges, Dave; Nakada, Daisuke et al. (2013) Inhibition of AMPK catabolic action by GSK3. Mol Cell 50:407-19
Fingar, Diane C; Inoki, Ken (2012) Deconvolution of mTORC2 "in Silico". Sci Signal 5:pe12
Inoki, Ken; Huber, Tobias B (2012) Mammalian target of rapamycin signaling in the podocyte. Curr Opin Nephrol Hypertens 21:251-7
Hong, Sungki; Mannan, Aristotle M; Inoki, Ken (2012) Evaluation of the nutrient-sensing mTOR pathway. Methods Mol Biol 821:29-44
Bridges, Dave; Fisher, Kaleigh; Zolov, Sergey N et al. (2012) Rab5 proteins regulate activation and localization of target of rapamycin complex 1. J Biol Chem 287:20913-21
Inoki, Ken; Mori, Hiroyuki; Wang, Junying et al. (2011) mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. J Clin Invest 121:2181-96

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