scholarly journals Rheb (Ras Homologue Enriched in Brain)-dependent Mammalian Target of Rapamycin Complex 1 (mTORC1) Activation Becomes Indispensable for Cardiac Hypertrophic Growth after Early Postnatal Period

2013 ◽  
Vol 288 (14) ◽  
pp. 10176-10187 ◽  
Author(s):  
Takahito Tamai ◽  
Osamu Yamaguchi ◽  
Shungo Hikoso ◽  
Toshihiro Takeda ◽  
Manabu Taneike ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Postnatal Period ◽  
Early Postnatal Period ◽  
Target Of Rapamycin ◽  
Hypertrophic Growth ◽  
Mtorc1 Activation

Mammalian target of rapamycin complex 1 activation in podocytes promotes cellular crescent formation

2014 ◽  
Vol 307 (9) ◽  
pp. F1023-F1032 ◽  
Author(s):  
Junhua Mao ◽  
Zhifeng Zeng ◽  
Zhuo Xu ◽  
Jiangzhong Li ◽  
Lei Jiang ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Hypoxia Inducible Factor ◽  
Target Of Rapamycin ◽  
Crescent Formation ◽  
Glomerular Diseases ◽  
Mtorc1 Signaling ◽  
Cellular Crescent ◽  
Underlying Mechanisms ◽  
Mtorc1 Activation ◽  
Glomerular Tuft

Podocytes play a key role in the formation of cellular crescents in experimental and human diseases. However, the underlying mechanisms for podocytes in promoting crescent formation need further investigation. Here, we demonstrated that mammalian target of rapamycin complex 1 (mTORC1) signaling was remarkably activated and hypoxia-inducible factor (HIF) 1α expression was largely induced in cellular crescents from patients with crescentic glomerular diseases. Specific deletion of Tsc1 in podocytes led to mTORC1 activation in podocytes and kidney dysfunction in mice. Interestingly, 33 of 36 knockouts developed cellular or mixed cellular and fibrous crescents at 7 wk of age (14.19 ± 3.86% of total glomeruli in knockouts vs. 0% in control littermates, n = 12–36, P = 0.04). All of the seven knockouts developed crescents at 12 wk of age (30.92 ± 11.961% of total glomeruli in knockouts vs. 0% in control littermates, n = 4–7, P = 0.002). Most notably, bridging cells between the glomerular tuft and the parietal basement membrane as well as the cellular crescents were immunostaining positive for WT1, p-S6, HIF1α, and Cxcr4. Furthermore, continuously administrating rapamycin starting at 7 wk of age for 5 wk abolished crescents as well as the induction of p-S6, HIF1α, and Cxcr4 in the glomeruli from the knockouts. Together, it is concluded that mTORC1 activation in podocytes promotes cellular crescent formation, and targeting this signaling may shed new light on the treatment of patients with crescentic glomerular diseases.

Mammalian target of rapamycin is activated in the kidneys of patients with scleroderma renal crisis

2019 ◽  
Vol 5 (2) ◽  
pp. 152-158
Author(s):  
Jessica Salituri ◽  
Natalie Patey ◽  
Tomoko Takano ◽  
Pierre Fiset ◽  
Sonia Del Rincon ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Vascular Lesions ◽  
Scleroderma Renal Crisis ◽  
Renal Vasculature ◽  
Renal Biopsies ◽  
Mtorc1 Activation ◽  
Arterial Endothelial Cells ◽  
Renal Crisis

Objectives: Scleroderma renal crisis is a rare but serious complication affecting 2%–15% of patients with systemic sclerosis. Despite treatment with angiotensin-converting enzyme inhibitors, outcomes for scleroderma renal crisis patients are still poor. The cellular signaling mechanisms in scleroderma renal crisis are not yet known. Mammalian target of rapamycin, comprised of the subunits mTORC1 and mTORC2, has been shown to be activated in vascular lesions of renal transplant patients with anti-phospholipid antibody syndrome. Given the similarities between the pathophysiology of scleroderma renal crisis and anti-phospholipid antibody syndrome, we hypothesized that the mammalian target of rapamycin pathway would also be activated in the renal vasculature of patients with scleroderma renal crisis. Methods: We retrospectively analyzed renal biopsies of five patients with scleroderma renal crisis in the Canadian Scleroderma Research Group cohort. Immunostaining was performed using anti-P-S6RP antibodies to evaluate the phosphorylation of mTORC1, and anti-Rictor and anti-S473 to determine activation of mTORC2. Results: Four of the five patients showed mTORC1 activation in arteriolar endothelial cells, and three of the five patients showed mTORC1 activation in the arterial endothelial cells. Two of four samples showed Rictor expression in the arteriolar and arterial endothelial cells, showing mTORC2 activation. There was no expression of mTORC1 or mTORC2 in samples from two healthy controls. Conclusion: We demonstrate that both mTORC1 and mTORC2 are activated in renal biopsies with typical histologic features of scleroderma renal crisis. Dual mammalian target of rapamycin inhibitors are currently available and in development. These findings could inform further research into novel treatment targets for scleroderma renal crisis.

scholarly journals mTORC1-IRE1α pathway activation contributes to palmitate-elicited triglyceride secretion and cell death in hepatocytes

2020 ◽  
Vol 245 (14) ◽  
pp. 1268-1279
Author(s):  
Jun Wang ◽  
Yingli Chen ◽  
Qing Song ◽  
Alexandra Griffiths ◽  
Zhenyuan Song
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Fatty Acid ◽  
Endoplasmic Reticulum Stress ◽  
Metabolic Disorders ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Specific Cell ◽  
Canonical Pathways ◽  
Mtorc1 Activation

Lipotoxicity, defined as the cell death and/or cellular dysfunction induced by ectopic lipid deposition, plays a pathological role in the development of many metabolic diseases. Although endoplasmic reticulum stress is a well-documented mechanism behind, how endoplasmic reticulum stress is initiated during lipotoxicity remains obscure. In this study, using palmitate exposure (a 16-C saturated fatty acid) of AML12 hepatocytes, a non-transformed murine hepatocyte cell line, as an experimental model, we identified mammalian target of rapamycin complex 1 (mTORC1) to be a critical contributor to palmitate-elicited lipotoxicity, manifested by incremental triglycerides secretion and cell death. Unlike oleate (an 18-C monounsaturated fatty acid), palmitate strongly induced mTORC1 activation in hepatocytes. Importantly, mTOR inhibitors, torin-1, and rapamycin prevented hepatocytes from palmitate-induced triglyceride overproduction and cell death. We further showed that the intracellular metabolism of palmitate is required for its stimulatory effect on mTORC1. Whereas the inhibition of long-chain acyl-CoA synthetase, which converts palmitate to palmitoyl-CoA, attenuated mTORC1 activation and protected against cell death, the inhibition of stearoyl-CoA desaturase-1, the enzyme desaturating palmitate to palmitoleate, strengthened mTORC1 activation and aggravated triglyceride overproduction and cell death. Our further investigations revealed that the palmitate-induced mTORC1 activation was required for its endoplasmic reticulum stress-inducing action as mTORC1 inhibition ablated palmitate-induced activation of IRE1α, one of the three canonical pathways activated during unfolded protein response. Finally, our data demonstrated that IRE1α inhibition ameliorated triglyceride overproduction and cell death in response to palmitate exposure. Collectively, our data identify that mTORC1-IRE1α pathway is coordinately implicated in the development of lipotoxicity in hepatocyte. Impact statement Lipotoxicity induced by saturated fatty acids (SFA) plays a pivotal role in the pathogenesis of a variety of obesity-related metabolic disorders; however, the exact mechanism(s) underlying lipotoxicity development remains elusive. The liver plays a central role in regulating intrahepatic and circulatory lipid homeostasis. In the current study, we identified that mammalian target of rapamycin complex 1 (mTORC1) activation plays an important role in regulating the detrimental effects of SFA palmitate in hepatocytes, in specific cell death, and TG overproduction. Furthermore, our data confirmed that palmitate-induced mTORC1 activation is attributable to its stimulatory effect on IRE1α, one of three canonical pathways activated during ER stress. Importantly, IRE1α inhibition prevented palmitate-triggered cell death and TG overproduction, suggesting mTORC1-IRE1α pathway is mechanistically implicated in palmitate lipotoxicity. The data obtained in the current investigation support future study to explore the therapeutic potential of targeting the mTORC1-IRE1α pathway as a novel clinical strategy for the treatment of metabolic disorders involving lipotoxicity.

scholarly journals Current Models of Mammalian Target of Rapamycin Complex 1 (mTORC1) Activation by Growth Factors and Amino Acids

2014 ◽  
Vol 15 (11) ◽  
pp. 20753-20769 ◽  
Author(s):  
Xu Zheng ◽  
Yan Liang ◽  
Qiburi He ◽  
Ruiyuan Yao ◽  
Wenlei Bao ◽  
...  
Keyword(s):  
Amino Acids ◽  
Growth Factors ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Mtorc1 Activation

scholarly journals Phosphorylation of Raptor by p38β Participates in Arsenite-induced Mammalian Target of Rapamycin Complex 1 (mTORC1) Activation

2011 ◽  
Vol 286 (36) ◽  
pp. 31501-31511 ◽  
Author(s):  
Xiao-Nan Wu ◽  
Xue-Kun Wang ◽  
Su-Qin Wu ◽  
Jiawei Lu ◽  
Min Zheng ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Mtorc1 Activation
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