Diabetic nephropathy (DN) is among the most lethal complications of type 1 and type 2 diabetes. The devastating effect of DN presents itself first as a major form of glomerulopathy and progresses to glomerulosclerosis, and ultimately leads to end-stage renal disease (ESRD). Recent investigations have revealed that injuries to podocytes play a critical role in the development of DN. We have identified aberrant activation of mammalian target of rapamycin complex 1 (mTORC1) in diabetic podocytes as a critical determinant for podocyte injury and the development of DN. The mTORC1 kinase complex functions to sense nutrient availability. However, the molecular mechanisms underlying the aberrant activation of mTORC1 in diabetic podocytes remain elusive. We discovered brain acid soluble protein1 (BASP1) as a potent mTORC1 activator. Previous studies have reported BASP1 expression in podocytes and elevated in the kidneys of diabetic patients. Importantly, we found that BASP1 expression is specifically enhanced in the podocytes of both type 1 and type 2 diabetic animals. Further, our biochemical data showed that BASP1 overexpression dramatically enhanced mTORC1 activity, while BASP1 knockdown significantly attenuated mTORC1 activity in multiple cell lines including podocytes. Interestingly, BASP1 knockdown dominantly inhibits nutrient- but not growth factor-induced mTORC1 activation, suggesting that BASP1 functions as a specific mTORC1 activator in response to nutrients and plays a key role in the activation of mTORC1 in diabetic podocytes. To explore this possibility in greater detail, we propose to elucidate the mechanisms by which BASP1 expression is enhanced in podocytes under diabetic conditions and determine how BASP1 supports nutrient-induced mTORC1 activation. Finally, we will evaluate the roles of BASP1 and nutrient-mediated mTORC1 activation in the development of DN using mouse models where BASP1 and the mTORC1- mediated nutrient sensing pathway are blocked through the podocyte-specific ablation of the BASP1 and p18 genes, respectively. Completion of this study promises to reveal novel molecular mechanisms underlying aberrant activation of mTORC1 in diabetic podocytes and provide potential pharmacologic targets for future therapies that attenuate mTORC1 signaling in diabetic podocytes and in the progression of DN.
Diabetic nephropathy (DN) is among the most lethal complications of type1 and type2 diabetes. It is characterized as a major glomerulopathy that develops into glomerulosclerosis, leading ultimately to end- stage renal disease (ESRD). Despite years of attention, the pathological mechanisms underlying the onset and/or development of this devastating complication remain incompletely understood. We have found that activation of mammalian target of rapamycin (mTOR), a nutrient sensing kinase, in glomerular epithelial cells plays an important pathological role in the development of DN. In this proposal, we will investigate the molecular mechanisms by which mTOR is activated in diabetic epithelial cells and provide valuable information to develop therapeutic approaches to attenuate aberrant activation of mTOR and the development of DN.
|Yao, Yao; Inoki, Ken (2016) The role of mechanistic target of rapamycin in maintenance of glomerular epithelial cells. Curr Opin Nephrol Hypertens 25:28-34|
|Yao, Yao; Wang, Junying; Yoshida, Sei et al. (2016) Role of Ragulator in the Regulation of Mechanistic Target of Rapamycin Signaling in Podocytes and Glomerular Function. J Am Soc Nephrol 27:3653-3665|
|Yoshida, Sei; Pacitto, Regina; Yao, Yao et al. (2015) Growth factor signaling to mTORC1 by amino acid-laden macropinosomes. J Cell Biol 211:159-72|
|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|
|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|
|Suzuki, Tsukasa; Bridges, Dave; Nakada, Daisuke et al. (2013) Inhibition of AMPK catabolic action by GSK3. Mol Cell 50:407-19|
|Inoki, Ken (2013) Proximal tubules forget ""self-eating"" when they meet Western meals. J Am Soc Nephrol 24:1711-3|
|Bridges, Dave; Ma, Jing-Tyan; Park, Sujin et al. (2012) Phosphatidylinositol 3,5-bisphosphate plays a role in the activation and subcellular localization of mechanistic target of rapamycin 1. Mol Biol Cell 23:2955-62|
|Fingar, Diane C; Inoki, Ken (2012) Deconvolution of mTORC2 ""in Silico"". Sci Signal 5:pe12|
Showing the most recent 10 out of 22 publications