Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Radiocontrast medium induced nephrotoxicity is a major clinical problem. There is considerable interest in reducing the incidence of acute renal failure due to the use of radiocontrast media (RCM). Reduction of renal blood flow and direct toxic effect on renal tubular epithelial cells have been postulated as major causes of RCM nephropathy. Understanding the molecular mechanisms by which RCM cause cell damage may allow the development of pharmacological therapy to prevent their nephrotoxicity. In this work we have investigated the signaling pathways that may be affected by RCM. The incubation of human renal tubular proximal cells with sodium diatrizoate, iopromide and iomeprol caused a marked dephosphorylation of the kinase Akt on Ser473 within 5min of incubation. RCM also caused a decrease in cell viability, which was substantially alleviated by transfecting the cells with a constitutively active form of Akt. Further downstream targets of Akt, including the Forkhead family of transcription factors FKHR and FKHRL1, were also dephosphorylated by RCM at Thr24 and Thr32, respectively. The P70S6 kinase was also dephosphorylated at Thr389 and Ser371 by RCM. However there was a more dramatic decrease in phosphorylation of the phosphorylated form of mammalian target of rapamycin (mTOR) and of the extracellular-signal regulated kinases (ERK) 1/2 caused by sodium diatrizoate than by iopromide. These results demonstrate the effect of RCM on some intracellular signaling pathways that may allow understanding of the mechanism of their toxicity and may allow the development of strategies to overcome their adverse effects.
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PMID:Radiocontrast media cause dephosphorylation of Akt and downstream signaling targets in human renal proximal tubular cells. 1698 77

Liver transplant recipients are at increasingly high risk for suffering from impaired renal function and probable need of renal replacement therapy. Extended criteria organs and transplantation of patients with higher model for end-stage liver disease scores further increase this problem. Acute and chronic nephrotoxicity are the trade-off in immunosuppression with potent calcineurin inhibitors (CNIs). As a good renal function is associated with better graft and patient survival, CNI minimization protocols have been developed. Current strategies to overcome CNI toxicity include reduction or withdrawal of CNIs concurrently with switching over to mammalian target of rapamycin inhibitor or mycophenolate mofetil (MMF)-based regimens. This strategy caused an improvement in renal function in a significant number of liver transplantation patients according to several studies. However, total CNI avoidance seems to result in higher rejection rates. To prevent chronic renal dysfunction in patients prone to or with acute renal failure, CNI delay - with induction therapy for bridging - followed by low-dose CNI in combination with MMF are proven strategies without risking higher rejection rates. An individualized, tailor-made immunosuppressive regime, with a special focus on renal function is recommended. This review gave an overview on CNI minimization protocols in liver transplantation also focusing on recently analyzed studies.
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PMID:Calcineurin inhibitor minimization protocols in liver transplantation. 1912 Nov 46

The mortality rate from acute kidney injury after major cardiovascular operations can be as high as 60%, and no therapies have been proved to prevent acute kidney injury in this setting. Here, we show that preconditioning with the anesthetic gas xenon activates hypoxia-inducible factor 1alpha (HIF-1alpha) and its downstream effectors erythropoietin and vascular endothelial growth factor in a time-dependent manner in the kidneys of adult mice. Xenon increased the efficiency of HIF-1alpha translation via modulation of the mammalian target of rapamycin pathway. In a model of renal ischemia-reperfusion injury, xenon provided morphologic and functional renoprotection; hydrodynamic injection of HIF-1alpha small interfering RNA demonstrated that this protection is HIF-1alpha dependent. These results suggest that xenon preconditioning is a natural inducer of HIF-1alpha and that administration of xenon before renal ischemia can prevent acute renal failure. If these data are confirmed in the clinical setting, then preconditioning with xenon may be beneficial before procedures that temporarily interrupt renal perfusion.
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PMID:Xenon preconditioning protects against renal ischemic-reperfusion injury via HIF-1alpha activation. 1914 58

The cumulative incidence of chronic kidney disease after liver transplantation (LT) is on the order of 40 to 50% at 1 year and over 50% at 5 years, and that of pre-end-stage renal failure 5-10% at 1 year and 10-20% at 5 and 10 years. Several variables appear to be independently associated with onset of kidney failure: age, sex (male), ethnicity (non-Asian), low glomerular filtration rate (GFR) before transplantation, use of renal replacement therapy before LT, diabetes before LT, HCV carriage, postoperative onset of acute renal failure, the year of transplantation (before or after 1994). Various factors cause chronic kidney disease after LT. Calcineurin inhibitors, specifically cyclosporine and tacrolimus, but also diabetes, nephroangiosclerosis, previous use of hydroxyethylstarch, play a major role in the onset of postgraft kidney failure. It is generally agreed that the nephrotoxicity of calcineurin inhibitors is in part dose-dependent and that a reduction in the dose can improve renal function. Nonetheless, the lesions are in large part irreversible. Trials are required to test interventions early after the LT, as soon as the first signs of kidney failure appear. Moreover, although the effect is dose-dependent, the relation with blood concentration of the drug is very imperfect, so any intervention must reduce the dose and not just the concentration to improve renal function. The introduction of new immunosuppressive drugs that are not nephrotoxic, such as mycophenolate mofetil, mTOR inhibitors, and anti-CD25 monoclonal antibodies [basiliximab and daclizumab (withdrawn from the market)], allow primary or secondary prevention of nephrotoxicity, with a partial or complete reduction in calcineurin inhibitors. Other interventions useful to limiting kidney failure after LT are the correction of hypertension, diabetes, and hyperlipidemia.
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PMID:[Renal failure following liver transplantation]. 1956 Aug 96

Renal function deteriorates in about half of patients undergoing other transplants. We report the results of 105 renal biopsies from 101 nonrenal transplant recipients (bone marrow 14, liver 41, lung 30, heart 20). Biopsy indications were protracted acute renal failure (9%), creatinine increases (83%), heavy proteinuria (22%), or renal insufficiency before re-transplantation (9%). Histological findings other than nonspecific chronic changes, hypertension-related damage, and signs of chronic CNI toxicity included primary glomerular disease (17%), mostly after liver transplantation (21%) or after bone marrow transplantation (29%), and thrombotic microangiopathy (TMA) namely (10%). TMA had the most serious impact on the clinical course. Besides severe hypertension, one TMA patient died of cerebral hemorrhage, 5 had hemolytic-uremic syndrome, and 6 rapidly developed end-stage renal failure. TMA patients had the shortest kidney survival post-biopsy and, together with patients with acute tubular injury, the shortest kidney and patient survival since transplantation. Nine TMA patients had received CNI, 3 of them concomitantly received an mTOR-inhibitor. CNI toxicity is implicated in most patients with renal failure after transplant of other organs and may play a role in the development of TMA, the most serious complication. However, decreased renal function should not be routinely ascribed to CNI.
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PMID:Biopsy-diagnosed renal disease in patients after transplantation of other organs and tissues. 2088 35

Renal ischemia/reperfusion (I/R) is a major cause of acute renal failure. Quercetin, a flavonoid antioxidant, presents in many kinds of food. The molecular mechanism of quercetin on renal protection during I/R is still unclear. Here, we investigated the role of AMP-activated protein kinase (AMPK)-regulated autophagy in renal protection by quercetin. To investigate whether quercetin protects renal cells from I/R-induced cell injury, an in vitro model of I/R and an in vivo I/R model were used. Cell apoptosis was determined by propidium iodide/annexin V staining. Western blotting and immunofluorescence were used to determine the autophagy. AMPK expression was inhibited with appropriate short hairpin RNA (shRNA). In cultured renal tubular cell I/R model, quercetin decreased the cell injury, up-regulated the AMPK phosphorylation, down-regulated the mammalian target of rapamycin (mTOR) phosphorylation and activated autophagy during I/R. Knockdown of AMPK by shRNA transfection decreased the quercetin-induced autophagy but did not affect the mTOR phosphorylation. In I/R mouse model, quercetin decreased the increased serum creatinine level and altered renal histological score. Quercetin also increased AMPK phosphorylation, inhibited the mTOR phosphorylation and activated autophagy in the kidneys of I/R mice. These results suggest that quercetin activates an AMPK-regulated autophagy signaling pathway, which offers a protective effect in renal I/R injury.
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PMID:Quercetin attenuates renal ischemia/reperfusion injury via an activation of AMP-activated protein kinase-regulated autophagy pathway. 2508 94

With the incorporation of targeted therapies in routine cancer therapy, it is imperative that the array of toxicities associated with these agents be well-recognized and managed, especially since these toxicities are distinct from those seen with conventional cytotoxic agents. This review will focus on these renal toxicities from commonly used targeted agents. This review discusses the mechanisms of these side effects and management strategies. Anti-vascular endothelial growth factor (VEGF) agents including the monoclonal antibody bevacizumab, aflibercept (VEGF trap), and anti-VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKIs) all cause hypertension, whereas some of them result in proteinuria. Monoclonal antibodies against the human epidermal growth factor receptor (HER) family of receptors, such as cetuximab and panitumumab, cause electrolyte imbalances including hypomagnesemia and hypokalemia due to the direct nephrotoxic effect of the drug on renal tubules. Cetuximab may also result in renal tubular acidosis. The TKIs, imatinib and dasatinib, can result in acute or chronic renal failure. Rituximab, an anti-CD20 monoclonal antibody, can cause acute renal failure following initiation of therapy because of the onset of acute tumor lysis syndrome. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, can result in proteinuria. Discerning the renal adverse effects resulting from these agents is essential for safe treatment strategies, particularly in those with pre-existing renal disease.
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PMID:Renal Toxicities of Targeted Therapies. 2592 90