Isoflurane activates intestinal sphingosine kinase to protect against bilateral nephrectomy-induced liver and intestine dysfunction

Kim, Minjae; Park, Sang Won; Kim, Mihwa; D’Agati, Vivette D.; Lee, H. Thomas

doi:10.1152/ajprenal.00467.2010

Cited by 27 publications

(17 citation statements)

References 58 publications

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“…Finally, systemic effects were only evaluated after one session of PD, and the lung was the only remote organ examined. Since animal models have demonstrated that AKI also adversely affects the heart 24 , liver 25,26 , brain 27 , and intestine 28 , future studies with more than one PD session and the effect of PD on other organ injuries would be of interest.…”

Section: Discussionmentioning

confidence: 99%

Early peritoneal dialysis reduces lung inflammation in mice with ischemic acute kidney injury

Altmann

Ahuja

Kiekhaefer

et al. 2017

Kidney International

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Although dialysis has been used in the care of patients with acute kidney injury (AKI) for over 50 years, very little is known about the potential benefits of uremic control on systemic complications of AKI. Since the mortality of AKI requiring renal replacement therapy (RRT) is greater than half in the intensive care unit a better understanding of the potential of RRT to improve outcomes is urgently needed. Therefore, we sought to develop a technically feasible and reproducible model of RRT in a mouse model of AKI. Models of low and high dose peritoneal dialysis (PD) were developed and their effect on AKI, systemic inflammation, and lung injury after ischemic AKI was examined. High dose PD had no effect on AKI, but effectively cleared serum IL-6, and dramatically reduced lung inflammation while low dose PD had no effect on any of these three outcomes. Both models of RRT using PD in AKI in mice reliably lowered urea in a dose dependent fashion. Thus, use of these models of PD in mice with AKI has great potential to unravel the mechanisms by which RRT may improve the systemic complications that have led to increased mortality in AKI. In light of recent data demonstrating reduced serum IL-6 and improved outcomes with prophylactic PD in children, we believe our results are highly clinically relevant.

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Section: Discussionmentioning

confidence: 99%

Early peritoneal dialysis reduces lung inflammation in mice with ischemic acute kidney injury

Altmann

Ahuja

Kiekhaefer

et al. 2017

Kidney International

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“…61 In addition, mice lacking the SK-1 enzyme were not protected against renal IR injury with isoflurane. 63 Volatile Anesthetics Induce Renal Tubular Adenosine Synthesis via Activation of CD73 It is becoming increasingly clear that volatile anesthetic-mediated TGF-b1 release activates additional cytoprotective pathways. We recently demonstrated that isoflurane-mediated release of TGFb1 induces CD73 synthesis in vivo as well as in vitro, leading to increased renal tubular adenosine generation.…”

Section: Volatile Anesthetics and Renal Protection Mechanismsmentioning

confidence: 99%

Volatile Anesthetics and AKI

Fukazawa

Lee

2014

Journal of the American Society of Nephrology

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AKI is a major clinical problem with extremely high mortality and morbidity. Kidney hypoxia or ischemia-reperfusion injury inevitably occurs during surgery involving renal or aortic vascular occlusion and is one of the leading causes of perioperative AKI. Despite the growing incidence and tremendous clinical and financial burden of AKI, there is currently no effective therapy for this condition. The pathophysiology of AKI is orchestrated by renal tubular and endothelial cell necrosis and apoptosis, leukocyte infiltration, and the production and release of proinflammatory cytokines and reactive oxygen species. Effective management strategies require multimodal inhibition of these injury processes. Despite the past theoretical concerns about the nephrotoxic effects of several clinically utilized volatile anesthetics, recent studies suggest that modern halogenated volatile anesthetics induce potent anti-inflammatory, antinecrotic, and antiapoptotic effects that protect against ischemic AKI. Therefore, the renal protective properties of volatile anesthetics may provide clinically useful therapeutic intervention to treat and/or prevent perioperative AKI. In this review, we outline the history of volatile anesthetics and their effect on kidney function, briefly review the studies on volatile anesthetic-induced renal protection, and summarize the basic cellular mechanisms of volatile anesthetic-mediated protection against ischemic AKI.

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“…For example, SphK1 upregulation was recently identified as the mechanism by which isoflurane, a volatile anesthetic, prevents intestinal inflammation and dysfunction after acute kidney injury (AKI) (Kim et al, 2011). In a bilateral nephrectomy model of AKI, isoflurane significantly attenuated multiple hallmarks of intestinal injury, including epithelial necrosis, villous swelling, apoptosis, vascular permeability, and expression of inflammatory cytokines (Kim et al, 2011). These protective effects were accompanied by increased SphK1 expression and S1P in small intestinal crypts, and were abrogated in mice receiving a SphK1 inhibitor prior to surgery (Kim et al, 2011).…”

Section: Targeting S1p Signaling In Diseasesmentioning

confidence: 99%

“…In a bilateral nephrectomy model of AKI, isoflurane significantly attenuated multiple hallmarks of intestinal injury, including epithelial necrosis, villous swelling, apoptosis, vascular permeability, and expression of inflammatory cytokines (Kim et al, 2011). These protective effects were accompanied by increased SphK1 expression and S1P in small intestinal crypts, and were abrogated in mice receiving a SphK1 inhibitor prior to surgery (Kim et al, 2011). However, a mechanism for the observed suppression of inflammatory signaling by isoflurane remains elusive.…”

Section: Targeting S1p Signaling In Diseasesmentioning

confidence: 99%

Development of small-molecule inhibitors of sphingosine-1-phosphate signaling

Edmonds

Milstien

Spiegel

2011

Pharmacology & Therapeutics

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The pleiotropic sphingolipid mediator, sphingosine-1-phosphate, produced in cells by two sphingosine kinase isoenzymes, SphK1 and SphK2, regulates many cellular and physiological processes important for homeostasis and development and pathophysiology. Many of the actions of S1P are mediated by a family of five specific cell surface receptors that are ubiquitously and specifically expressed, although important direct intracellular targets of S1P have also recently been identified. S1P, SphK1, and or S1P receptors have been linked to onset and progression of numerous diseases, including many types of cancer, and especially inflammatory disorders, such as multiple sclerosis, asthma, rheumatoid arthritis, inflammatory bowel disease, and sepsis. S1P formation and signaling are attractive targets for development of new therapeutics. The effects of a number of inhibitors of SphKs and S1PRs have been examined in animal models of human diseases. The effectiveness of the immunosuppressant FTY720 (known as Fingolomod or Gilenya), recently approved for the treatment of multiple sclerosis, whose actions are mediated by downregulation of S1PR1, has become the gold standard for S1P-centric drugs. Here, we review S1P biology and signaling with an emphasis on potential therapeutic benefits of specific interventions and discuss recent development of small molecule antagonists and agonists that target specific subtypes of S1P receptors as well as inhibitors of SphKs.

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Isoflurane activates intestinal sphingosine kinase to protect against bilateral nephrectomy-induced liver and intestine dysfunction

Cited by 27 publications

References 58 publications

Early peritoneal dialysis reduces lung inflammation in mice with ischemic acute kidney injury

Early peritoneal dialysis reduces lung inflammation in mice with ischemic acute kidney injury

Volatile Anesthetics and AKI

Development of small-molecule inhibitors of sphingosine-1-phosphate signaling

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