Role of mechanistic target of rapamycin (mTOR) in renal function and ischaemia-reperfusion induced kidney injury

2016 ◽  
Vol 43 (11) ◽  
pp. 1087-1096 ◽  
Author(s):  
Reem Alshaman ◽  
Luan Truong ◽  
Adebayo Oyekan
Keyword(s):  
Renal Function ◽  
Kidney Injury ◽  
Target Of Rapamycin ◽  
Mechanistic Target Of Rapamycin ◽  
Ischaemia Reperfusion

scholarly journals The Role of Dexmedetomidine for the Prevention of Acute Kidney Injury in Critical Care

2021 ◽  
pp. 97-106
Author(s):  
Gion Ruegg ◽  
Nora Luethi ◽  
Luca Cioccari
Keyword(s):  
Experimental Data ◽  
Intensive Care Unit ◽  
Acute Kidney Injury ◽  
Clinical Trials ◽  
Renal Function ◽  
Critical Care ◽  
Intensive Care ◽  
Kidney Injury ◽  
Ischaemia Reperfusion

Acute kidney injury (AKI) occurs in up to 50% of patients admitted to the intensive care unit and is associated with increased mortality. Currently, there is no effective pharmacotherapy for prevention or treatment of AKI. In animal models of sepsis and ischaemia-reperfusion, α2-agonists like dexmedetomidine (DEX) exhibit anti-inflammatory properties and experimental data indicate a potential protective effect of DEX on renal function. However, clinical trials have yielded inconsistent results in critically ill patients. This review discusses the pathophysiological mechanisms involved in AKI, the renal effects of DEX in various intensive care unit-related conditions, and summarises the available literature addressing the use of DEX for the prevention of AKI.

scholarly journals GLP-1 receptor agonist ameliorates obesity-induced chronic kidney injury via restoring renal lipid and energy metabolism homeostasis: revealed by metabolomics

2017 ◽  
Author(s):  
Chengshi Wang ◽  
Ling Li ◽  
Shuyun Liu ◽  
Guangneng Liao ◽  
Younan Chen ◽  
...  
Keyword(s):  
Renal Function ◽  
Energy Metabolism ◽  
High Fat Diet ◽  
Receptor Agonist ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Direct Role ◽  
Chronic Kidney Injury ◽  
Metabolomic Data

AbstractIncreasing evidence indicate that obesity is highly associated with chronic kidney disease (CKD).GLP-1 receptor (GLP-1R) agonist has shown benefits on kidney diseases, but its direct role on kidney metabolism in obesity is still not clear. This study aims to investigate the protection and metabolic modulation role of liraglutide (Lira) on kidney of obesity. Rats were induced obese by high-fat diet (HFD), and renal function and metabolism changes were evaluated by metabolomic, biological and histological methods. HFD rats exhibited metabolic disorders including elevated body weight, hyperlipidemia and impaired glucose tolerance, and remarkable renal injuries including declined renal function and inflammatory/fibrotic changes, whereas Lira significantly ameliorated these adverse effects in HFD rats. Metabolomic data showed that Lira reduced renal lipids including fatty acid residues, cholesterol, phospholipids and triglycerides, and improved mitochondria metabolites such as succinate, citrate, taurine, fumarate and NAD+ in the kidney of HDF rats. Furthermore, we revealed that Lira inhibited renal lipid accumulation by coordinating lipogenic and lipolytic signals, and rescued renal mitochondria function via Sirt1/AMPK/PGC1α pathways in HDF rats. This study suggested that Lira alleviated HFD-induced kidney injury via directly restoring renal lipid and energy metabolism, and GLP-1 receptor agonist is a promising therapy for obesity-associated CKD.

scholarly journals Regulation of protein kinase Cδ Nuclear Import and Apoptosis by Mechanistic Target of Rapamycin Complex-1

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Antonio Layoun ◽  
Alexander A. Goldberg ◽  
Ayesha Baig ◽  
Mikaela Eng ◽  
Ortal Attias ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Nuclear Import ◽  
Target Of Rapamycin ◽  
Interferon Β ◽  
Structural Mechanism ◽  
Mechanistic Target Of Rapamycin ◽  
Kinase C ◽  
Nuclear Content ◽  
In Cells

AbstractInactivation of the protein complex ‘mechanistic target of rapamycin complex 1’ (mTORC1) can increase the nuclear content of transcriptional regulators of metabolism and apoptosis. Previous studies established that nuclear import of signal transducer and activator of transcription-1 (STAT1) requires the mTORC1-associated adaptor karyopherin-α1 (KPNA1) when mTORC1 activity is reduced. However, the role of other mTORC1-interacting proteins in the complex, including ‘protein kinase C delta’ (PKCδ), have not been well characterized. In this study, we demonstrate that PKCδ, a STAT1 kinase, contains a functional ‘target of rapamycin signaling’ (TOS) motif that directs its interaction with mTORC1. Depletion of KPNA1 by RNAi prevented the nuclear import of PKCδ in cells exposed to the mTORC1 inhibitor rapamycin or amino acid restriction. Mutation of the TOS motif in PKCδ led to its loss of regulation by mTORC1 or karyopherin-α1, resulting in increased constitutive nuclear content. In cells expressing wild-type PKCδ, STAT1 activity and apoptosis were increased by rapamycin or interferon-β. Those expressing the PKCδ TOS mutant exhibited increased STAT1 activity and apoptosis; further enhancement by rapamycin or interferon-β, however, was lost. Therefore, the TOS motif in PKCδ is a novel structural mechanism by which mTORC1 prevents PKCδ and STAT1 nuclear import, and apoptosis.

scholarly journals Pretreatment with Roxadustat (FG-4592) Attenuates Folic Acid-Induced Kidney Injury through Antiferroptosis via Akt/GSK-3β/Nrf2 Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-17 ◽  
Author(s):  
Xue Li ◽  
Yu Zou ◽  
Jia Xing ◽  
Yuan-Yuan Fu ◽  
Kai-Yue Wang ◽  
...  
Keyword(s):  
Renal Function ◽  
Folic Acid ◽  
Nuclear Translocation ◽  
Early Stage ◽  
Kidney Injury ◽  
Protective Role ◽  
Iron Accumulation ◽  
Inflammatory Factors ◽  
Nrf2 Activation

Folic acid- (FA-) induced kidney injury is characterized by the tubule damage due to the disturbance of the antioxidant system and subsequent interstitial fibrosis. FG-4592 is an inhibitor of prolyl hydroxylase of hypoxia-inducible factor (HIF), an antioxidant factor. The present study investigated the protective role of FG-4592 pretreatment at the early stage of the kidney injury and long-term impact on the progression of renal fibrosis. FG-4592 was administrated two days before FA injection in mice. On the second day after FA injection, the mice with FG-4592 pretreatment showed an improved renal function, compared with those without FG-4592 pretreatment, indicated by biochemical and histological parameters; meanwhile, the cellular content of iron, malondialdehyde, and 4-hydroxynonenal histologically decreased, implying the suppression of iron accumulation and lipid peroxidation. Simultaneously, upregulation of HIF-1α was found, along with Nrf2 activation, which was reflected by increased nuclear translocation and high-expression of downstream proteins, including heme-oxygenase1, glutathione peroxidase4, and cystine/glutamate transporter, as well as ferroportin. Correspondingly, the elevated levels of antioxidative enzymes and glutathione, as well as reduced iron accumulation, were observed, suggesting a lower risk of occurrence of ferroptosis with FG-4592 pretreatment. This was confirmed by reversed pathological parameters and improved renal function in FA-treated mice with the administration of ferrostatin-1, a specific ferroptosis inhibitor. Furthermore, a signal pathway study indicated that Nrf2 activation was associated with increased phosphorylation of Akt and GSK-3β, verified by the use of an inhibitor of the PI3K that phosphorylates Akt. Moreover, FG-4592 pretreatment also decreased macrophage infiltration and expression of inflammatory factors TNF-α and IL-1β. On the 14th day after FA injection, FG-4592 pretreatment decreased collagen deposition and expression of fibrosis biomarkers. These findings suggest that the protective role of FG-4592 pretreatment is achieved mainly by decreasing ferroptosis at the early stage of FA-induced kidney injury via Akt/GSK-3β-mediated Nrf2 activation, which retards the fibrosis progression.

scholarly journals Chronic Kidney Disease, Obesity, and Hypertension: The Role of Leptin and Adiponectin

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
M. Tesauro ◽  
A. Mascali ◽  
O. Franzese ◽  
S. Cipriani ◽  
C. Cardillo ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Renal Function ◽  
Kidney Disease ◽  
Kidney Injury ◽  
Public Health Problem ◽  
Major Public Health Problem ◽  
Renal Progression ◽  
Obesity Hypertension ◽  
Progression Factor

Chronic kidney disease is a major public health problem and characterized by a progressive loss in renal function over a period of months or years as defined by structural or functional abnormalities of the kidney. Several elements contribute to determine a progression of the kidney injury, inducing a worsening of renal damage and accelerating the decline of renal function: obesity and hypertension are two known factors of kidney progression. Remarkable improvements have been recently achieved in the study of the endocrine features of the adipose tissue and have been able to produce hormone-like peptides named adipokines or adipocytokines. Among these adipocytokines, which represent a link between obesity, hypertension, and chronic nephropathy, leptins and adiponectin appear to play an important role. Leptin not only is a prohypertension element (renal progression factor) through the activation sympathetic nervous, but also is able to induce prosclerotic effects directly on the kidney. In contrast, a decline of adiponectin levels has been shown to be related to a picture of hypertension: an endothelial dysfunction has been described as the main pathogenic mechanism responsible for this phenomenon.

scholarly journals Mechanistic Target of Rapamycin Complex 2 Regulation of the Primary Human Trophoblast Cell Transcriptome

2021 ◽  
Vol 9 ◽  
Author(s):  
Fredrick J. Rosario ◽  
Amy Catherine Kelly ◽  
Madhulika B. Gupta ◽  
Theresa L. Powell ◽  
Laura Cox ◽  
...  
Keyword(s):  
Protein Expression ◽  
Gene Array ◽  
Target Of Rapamycin ◽  
Human Trophoblast ◽  
Mechanistic Target Of Rapamycin ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Cell Transcriptome ◽  
Pathway Analyses

Mechanistic Target of Rapamycin Complex 2 (mTORC2) regulates placental amino acid and folate transport. However, the role of mTORC2 in modulating other placental functions is largely unexplored. We used a gene array following the silencing of rictor to identify genes regulated by mTORC2 in primary human trophoblast (PHT) cells. Four hundred and nine genes were differentially expressed; 102 genes were down-regulated and 307 up-regulated. Pathway analyses demonstrated that inhibition of mTORC2 resulted in increased expression of genes encoding for pro-inflammatory IL-6, VEGF-A, leptin, and inflammatory signaling (SAPK/JNK). Furthermore, down-regulated genes were functionally enriched in genes involved in angiogenesis (Osteopontin) and multivitamin transport (SLC5A6). In addition, the protein expression of leptin, VEGFA, IL-6 was increased and negatively correlated to mTORC2 signaling in human placentas collected from pregnancies complicated by intrauterine growth restriction (IUGR). In contrast, the protein expression of Osteopontin and SLC5A6 was decreased and positively correlated to mTORC2 signaling in human IUGR placentas. In conclusion, mTORC2 signaling regulates trophoblast expression of genes involved in inflammation, micronutrient transport, and angiogenesis, representing novel links between mTOR signaling and multiple placental functions necessary for fetal growth and development.

Role of mTor signaling for tubular function and disease

Physiology ◽  
2021 ◽  
Author(s):  
Florian Grahammer ◽  
Tobias B Huber ◽  
Ferruh Artunc
Keyword(s):  
Diabetic Nephropathy ◽  
Actin Cytoskeleton ◽  
Mtor Signaling ◽  
Tubular Function ◽  
Target Of Rapamycin ◽  
Multiprotein Complexes ◽  
Mechanistic Target Of Rapamycin ◽  
Transport Regulation ◽  
Disease Entities

The mechanistic target of rapamycin (mTOR) forms two distinct intracellular multiprotein complexes that control a multitude of intracellular processes linked to metabolism, proliferation, actin cytoskeleton and survival. Recent studies have identified the importance of these complexes for transport regulation of ions and nutrients along the entire nephron. First reports could link altered activity of these complexes to certain disease entities i.e. diabetic nephropathy, AKI or hyperkalemia.

scholarly journals Macrophage Trafficking as Key Mediator of Adenine-Induced Kidney Injury

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Matheus Correa-Costa ◽  
Tárcio Teodoro Braga ◽  
Raphael José Ferreira Felizardo ◽  
Vinícius Andrade-Oliveira ◽  
Katia Regina Perez ◽  
...  
Keyword(s):  
Renal Function ◽  
Renal Dysfunction ◽  
Experimental Model ◽  
Interstitial Nephritis ◽  
Renal Injury ◽  
Kidney Injury ◽  
Renal Tissue ◽  
Special Role ◽  
Clodronate Liposome

Macrophages play a special role in the onset of several diseases, including acute and chronic kidney injuries. In this sense, tubule interstitial nephritis (TIN) represents an underestimated insult, which can be triggered by different stimuli and, in the absence of a proper regulation, can lead to fibrosis deposition. Based on this perception, we evaluated the participation of macrophage recruitment in the development of TIN. Initially, we provided adenine-enriched food to WT and searched for macrophage presence and action in the kidney. Also, a group of animals were depleted of macrophages with the clodronate liposome while receiving adenine-enriched diet. We collected blood and renal tissue from these animals and renal function, inflammation, and fibrosis were evaluated. We observed higher expression of chemokines in the kidneys of adenine-fed mice and a substantial protection when macrophages were depleted. Then, we specifically investigated the role of some key chemokines, CCR5 and CCL3, in this TIN experimental model. Interestingly, CCR5 KO and CCL3 KO animals showed less renal dysfunction and a decreased proinflammatory profile. Furthermore, in those animals, there was less profibrotic signaling. In conclusion, we can suggest that macrophage infiltration is important for the onset of renal injury in the adenine-induced TIN.

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