scholarly journals Inhibition of mammalian target of rapamycin decreases intrarenal oxygen availability and alters glomerular permeability

2018 ◽  
Vol 314 (5) ◽  
pp. F864-F872 ◽  
Author(s):  
Ebba Sivertsson ◽  
Malou Friederich-Persson ◽  
Carl M. Öberg ◽  
Angelica Fasching ◽  
Peter Hansell ◽  
...  

An increased kidney oxygen consumption causing tissue hypoxia has been suggested to be a common pathway toward chronic kidney disease. The mammalian target of rapamycin (mTOR) regulates cell proliferation and mitochondrial function. mTOR inhibitors (e.g., rapamycin) are used clinically to prevent graft rejection. mTOR has been identified as a key player in diabetes, which has stimulated the use of mTOR inhibitors to counter diabetic nephropathy. However, the effect of mTOR inhibition on kidney oxygen consumption is unknown. Therefore, we investigated the effects of mTOR inhibition on in vivo kidney function, oxygen homeostasis, and glomerular permeability. Control and streptozotocin-induced diabetic rats were chronically treated with rapamycin, and the functional consequences were studied 14 days thereafter. In both groups, mTOR inhibition induced mitochondrial uncoupling, resulting in increased total kidney oxygen consumption and decreased intrarenal oxygen availability. Concomitantly, mTOR inhibition induced tubular injury, as estimated from urinary excretion of kidney injury molecule-1 (KIM-1) and reduced urinary protein excretion. The latter corresponded to reduced sieving coefficient for large molecules. In conclusion, mTOR inhibition induces mitochondrial dysfunction leading to decreased oxygen availability in normal and diabetic kidneys, which translates into increased KIM-1 in the urine. Reduced proteinuria after mTOR inhibition is an effect of reduced glomerular permeability for large molecules. Since hypoxia has been suggested as a common pathway in the development of chronic kidney disease, mTOR inhibition to patients with preexisting nephropathy should be used with caution, since it may accelerate the progression of the disease.

2018 ◽  
Vol 115 (43) ◽  
pp. E10069-E10078 ◽  
Author(s):  
Guoli Shi ◽  
Stosh Ozog ◽  
Bruce E. Torbett ◽  
Alex A. Compton

Rapamycin and its derivatives are specific inhibitors of mammalian target of rapamycin (mTOR) kinase and, as a result, are well-established immunosuppressants and antitumorigenic agents. Additionally, this class of drug promotes gene delivery by facilitating lentiviral vector entry into cells, revealing its potential to improve gene therapy efforts. However, the precise mechanism was unknown. Here, we report that mTOR inhibitor treatment results in down-regulation of the IFN-induced transmembrane (IFITM) proteins. IFITM proteins, especially IFITM3, are potent inhibitors of virus–cell fusion and are broadly active against a range of pathogenic viruses. We found that the effect of rapamycin treatment on lentiviral transduction is diminished upon IFITM silencing or knockout in primary and transformed cells, and the extent of transduction enhancement depends on basal expression of IFITM proteins, with a major contribution from IFITM3. The effect of rapamycin treatment on IFITM3 manifests at the level of protein, but not mRNA, and is selective, as many other endosome-associated transmembrane proteins are unaffected. Rapamycin-mediated degradation of IFITM3 requires endosomal trafficking, ubiquitination, endosomal sorting complex required for transport (ESCRT) machinery, and lysosomal acidification. Since IFITM proteins exhibit broad antiviral activity, we show that mTOR inhibition also promotes infection by another IFITM-sensitive virus, Influenza A virus, but not infection by Sendai virus, which is IFITM-resistant. Our results identify the molecular basis by which mTOR inhibitors enhance virus entry into cells and reveal a previously unrecognized immunosuppressive feature of these clinically important drugs. In addition, this study uncovers a functional convergence between the mTOR pathway and IFITM proteins at endolysosomal membranes.


2009 ◽  
Vol 16 (3) ◽  
pp. 1017-1027 ◽  
Author(s):  
Alexander Gorshtein ◽  
Hadara Rubinfeld ◽  
Efrat Kendler ◽  
Marily Theodoropoulou ◽  
Vesna Cerovac ◽  
...  

The effect of mammalian target of rapamycin (mTOR) inhibitors on pituitary tumors is unknown. Akt overexpression was demonstrated in pituitary adenomas, which may render them sensitive to the anti-proliferative effects of these drugs. The objective of the study was to evaluate the anti-proliferative efficacy of the mTOR inhibitor, rapamycin, and its orally bioavailable analog RAD001 on the GH-secreting pituitary tumor GH3 and MtT/S cells and in human GH-secreting pituitary adenomas (GH-omas) in primary cell cultures. Treatment with rapamycin or RAD001 significantly decreased the number of viable cells and cell proliferation in a dose- and time-dependent manner. This was reflected by decreased phosphorylation levels of the downstream mTOR target p70S6K. Rapamycin treatment of GH3 cells induced G0/G1 cell cycle arrest. In other tumor cell types, this was attributed to a decrease in cyclin D1 levels. However, rapamycin did not affect cyclin D1 protein levels in GH3 cells. By contrast, it decreased cyclin D3 and p21/CIP, which stabilizes cyclin D/cyclin-dependent kinase 4 (cdk4) complexes. Rapamycin inhibited FCS-induced retinoblastoma phosphorylation and subsequent E2F-transcriptional activity. In response to decreased E2F activity, the expression of the E2F-regulated genes cyclin E and cdk2 was reduced. Our results showed that mTOR inhibitors potently inhibit pituitary cell proliferation, suggesting that mTOR inhibition may be a promising anti-proliferative therapy for pituitary adenomas. This therapeutic manipulation may have beneficial effects particularly for patients harboring invasive pituitary tumors resistant to current treatments.


Praxis ◽  
2009 ◽  
Vol 98 (25) ◽  
pp. 1511-1516
Author(s):  
Serra ◽  
Wüthrich

Die autosomal dominante polyzystische Nierenerkrankung (autosomal dominant polycystic kidney disease, ADPKD) ist charakterisiert durch eine massive Vergrösserung beider Nieren, bedingt durch unzählige Zysten. Die Zystenbildung beginnt bereits in utero und das kontinuierliche Zystenwachstum führt zur Kompression und Zerstörung des nicht-zystischen Nierenparenchyms, sodass schliesslich ein Nierenersatz in der 5. bis 6. Lebensdekade notwendig wird. Bisher gab es keine kausale Therapie, welche das Fortschreiten der Krankheiten aufhält. Tierexperimentelle Daten zeigen, dass die medikamentöse Inhibition eines zentralen Regulators der Zellproliferation, dem so genannten «mammalian target of rapamycin» (mTOR), den Kranheitsverlauf der ADPKD verlangsamen kann. Die vorliegende Übersicht vermittelt einen Einblick in die Erkrankung und in die neue therapeutische Möglichkeit des mTOR Inhibitors Sirolimus, welcher zurzeit in klinischen Studien getestet wird.


2007 ◽  
Vol 27 (21) ◽  
pp. 7405-7413 ◽  
Author(s):  
Xuerong Wang ◽  
Ping Yue ◽  
Chi-Bun Chan ◽  
Keqiang Ye ◽  
Takeshi Ueda ◽  
...  

ABSTRACT The initiation factor eukaryotic translation initiation factor 4E (eIF4E) plays a critical role in initiating translation of mRNAs, including those encoding oncogenic proteins. Therefore, eIF4E is considered a survival protein involved in cell cycle progression, cell transformation, and apoptotic resistance. Phosphorylation of eIF4E (usually at Ser209) increases its binding affinity for the cap of mRNA and may also favor its entry into initiation complexes. Mammalian target of rapamycin (mTOR) inhibitors suppress cap-dependent translation through inhibition of the phosphorylation of eIF4E-binding protein 1. Paradoxically, we have shown that inhibition of mTOR signaling increases eIF4E phosphorylation in human cancer cells. In this study, we focused on revealing the mechanism by which mTOR inhibition increases eIF4E phosphorylation. Silencing of either mTOR or raptor could mimic mTOR inhibitors’ effects to increase eIF4E phosphorylation. Moreover, knockdown of mTOR, but not rictor or p70S6K, abrogated rapamycin's ability to increase eIF4E phosphorylation. These results indicate that mTOR inhibitor-induced eIF4E phosphorylation is secondary to mTOR/raptor inhibition and independent of p70S6K. Importantly, mTOR inhibitors lost their ability to increase eIF4E phosphorylation only in cells where both Mnk1 and Mnk2 were knocked out, indicating that mTOR inhibitors increase eIF4E phosphorylation through a Mnk-dependent mechanism. Given that mTOR inhibitors failed to increase Mnk and eIF4E phosphorylation in phosphatidylinositol 3-kinase (PI3K)-deficient cells, we conclude that mTOR inhibition increases eIF4E phosphorylation through a PI3K-dependent and Mnk-mediated mechanism. In addition, we also suggest an effective therapeutic strategy for enhancing mTOR-targeted cancer therapy by cotargeting mTOR signaling and Mnk/eIF4E phosphorylation.


2020 ◽  
Author(s):  
Irene Paterniti ◽  
Michela Campolo ◽  
Giovanna Casili ◽  
Marika Lanza ◽  
Alessia Filippone ◽  
...  

Abstract Traumatic brain injury (TBI) induce primary and secondary damage on endothelium and brain parenchyma, leading neurons die rapidly by necrosis. The mammalian target of rapamycin signalling pathway (mTOR) mediates many aspects of cell growth and regeneration and is up-regulated after moderate to severe traumatic brain injury (TBI). The significance of this increased signalling event for recovery of brain function is presently unclear, here we used two different selective inhibitors of mTOR activity to explore the functional role of mTOR inhibition in an validated model of TBI, the controlled cortical impact injury (CCI). We treated animals withKU0063794, a dual mTORC1 and mTORC2 inhibitor, and with rapamycin a well-known inhibitor of mTOR, 1 and 4 hours after TBI. Our results demonstrated that mTOR inhibitors, especially KU0063794, significantly improve motor and cognitive recovery after TBI as well as reduce lesion volumes. Moreover we observed that mTOR inhibitors treatment ameliorate the neuroinflammation associated to TBI and showed that this acute treatment significantly diminished the extent of neuronal death, astrogliosis and apoptotic process after trauma. Our findings suggest that the neuronal mTORC1/2 activity after TBI is deleterious to brain function and acute intervention with selective mTORC1/2 inhibitor may represent an effective therapeutic strategy to improve recovery after brain trauma.


2008 ◽  
Vol 6 (S5) ◽  
pp. S-1-S-20 ◽  
Author(s):  
Robert A. Figlin ◽  
Elizabeth Brown ◽  
Andrew J. Armstrong ◽  
Wallace Akerley ◽  
Al B. Benson ◽  
...  

The mammalian target of rapamycin (mTOR) protein complex functions as an integration center for various intracellular signaling pathways involving cell cycle progression, proliferation, and angiogenesis. These pathways are frequently dysregulated in cancer, and therefore mTOR inhibition is a potentially important antitumor target. Commercially available mTOR inhibitors include rapamycin (i.e., sirolimus) and temsirolimus. Other agents under investigation include everolimus and deforolimus. mTOR inhibition has been studied in various solid tumors, including breast, gynecologic, gastrointestinal, prostate, lung, and head and neck cancers. Studies have focused on mTOR inhibition as a monotherapy or in combination with other drugs based on the principle that inhibiting as many targets as possible reduces the emergence of drug resistance. Temsirolimus is currently the only mTOR inhibitor that is specifically labeled for treatment of solid tumors. However, preclinical studies and early-phase trials are rapidly evolving. Additionally, research is further defining the complicated mTOR pathways and how they may be disordered in specific malignancies. To address these issues, NCCN convened a task force to review the underlying physiology of mTOR and related cellular pathways, and to review the current status of research of mTOR inhibition in solid tumors. (JNCCN 2008;6[Suppl 5]:S1—S20)


2010 ◽  
Vol 299 (6) ◽  
pp. F1365-F1373 ◽  
Author(s):  
Aihua Deng ◽  
Mary Ann K. Arndt ◽  
Joseph Satriano ◽  
Prabhleen Singh ◽  
Timo Rieg ◽  
...  

The 5/6thnephrectomy or ablation/infarction (A/I) preparation has been used as a classic model of chronic kidney disease (CKD). We observed increased kidney oxygen consumption (QO2) and altered renal hemodynamics in the A/I kidney that were normalized after combined angiotensin II (ANG II) blockade. Studies suggest hypoxia inducible factor as a protective influence in A/I. We induced hypoxia-inducible factor (HIF) and HIF target proteins by two different methods, cobalt chloride (CoCl2) and dimethyloxalyglycine (DMOG), for the first week after creation of A/I and compared the metabolic and renal hemodynamic outcomes to combined ANG II blockade. We also examined the HIF target proteins expressed by using Western blots and real-time PCR. Treatment with DMOG, CoCl2, and ANG II blockade normalized kidney oxygen consumption factored by Na reabsorption and increased both renal blood flow and glomerular filtration rate. At 1 wk, CoCl2and DMOG increased kidney expression of HIF by Western blot. In the untreated A/I kidney, VEGF, heme oxygenase-1, and GLUT1 were all modestly increased. Both ANG II blockade and CoCl2therapy increased VEGF and GLUT1 but the cobalt markedly so. ANG II blockade decreased heme oxygenase-1 expression while CoCl2increased it. By real-time PCR, erythropoietin and GLUT1 were only increased by CoCl2therapy. Cell proliferation was modestly increased by ANG II blockade but markedly after cobalt therapy. Metabolic and hemodynamic abnormalities were corrected equally by ANG II blockade and HIF therapies. However, the molecular patterns differed significantly between ANG II blockade and cobalt therapy. HIF induction may prove to be protective in this model of CKD.


2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Hernán Trimarchi ◽  
Mariano Forrester ◽  
Fernando Lombi ◽  
Vanesa Pomeranz ◽  
Romina Iriarte ◽  
...  

Primary glomerulonephritis stands as the third most important cause of end-stage renal disease, suggesting that appropriate treatment may not be as effective as intended to be. Moreover, proteinuria, the hallmark of glomerular damage and a prognostic marker of renal damage progression, is frequently resistant to thorough control. In addition, proteinuria may be the common end pathway in which different pathogenetic mechanisms may converge. This explains why immunosuppressive and nonimmunosuppressive approaches are partly not sufficient to halt disease progression. One of the commonest causes of primary glomerulonephritis is mesangioproliferative glomerulonephritis. Among the triggered intracellular pathways involved in mesangial cell proliferation, the mammalian target of rapamycin (mTOR) plays a critical role in cell growth, in turn regulated by many cytokines, disbalanced by the altered glomerulopathy itself. However, when inhibition of mTOR was studied in rodents and in humans with primary glomerulonephritis the results were contradictory. In light of these controversial data, we propose an explanation for these results, to dilucidate under which circumstances mTOR inhibition should be considered to treat glomerular proteinuria and finally to propose mTOR inhibitors to be prospectively assessed in clinical trials in patients with primary mesangioproliferative glomerulonephritis, for which a satisfactory standard immunosuppressive regimen is still pending.


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