| Isoflurane via TGF-beta1 release increases caveolae formation and organizes sphingosine kinase signaling in renal proximal tubules. | |
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MedLine Citation:
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PMID: 20053797 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We previously showed that the inhalational anesthetic isoflurane protects against renal proximal tubule necrosis via isoflurane-mediated stimulation and translocation of sphingosine kinase-1 (SK1) with subsequent synthesis of sphingosine-1-phosphate (S1P) in renal proximal tubule cells (Kim M, Kim M, Kim N, D'Agati VD, Emala CW Sr, Lee HT. Am J Physiol Renal Physiol 293: F1827-F1835, 2007). We also demonstrated that the anti-necrotic and anti-inflammatory effect of isoflurane is due in part to phosphatidylserine (PS) externalization and subsequent release of transforming growth factor-beta1 (TGF-beta1) (Lee HT, Kim M, Kim J, Kim N, Emala CW. Am J Nephrol 27: 416-424, 2007). In this study, we tested the hypothesis that isoflurane, via TGF-beta1 release, increases caveolae formation in the buoyant fraction of the cell membrane of human renal proximal tubule (HK-2) cells to organize SK1 and S1P signaling. To detect SK1 protein in the caveolae/caveolin fractions, we overexpressed human SK1 in HK-2 cells (SK1-HK-2). SK1-HK-2 cells exposed to isoflurane increased caveolae/caveolin formation in the buoyant membrane fractions which contained key signaling intermediates involved in isoflurane-mediated renal tubule protection, including S1P, SK1, ERK MAPK, and TGF-beta1 receptors. Furthermore, treating SK1-HK-2 cells with recombinant TGF-beta1 or PS liposome mixture increased caveolae formation, mimicking the effects of isoflurane. Conversely, TGF-beta1-neutralizing antibody blocked the increase in caveolae formation induced by isoflurane in SK1-HK-2 cells. The increase in SK1 activity in the caveolae-enriched fractions from isoflurane-treated nonlentivirus-infected HK-2 cells, while smaller in magnitude, was qualitatively similar to that found in the SK1-HK-2 cell line. Finally, isoflurane also increased caveolae formation in the kidneys of TGF-beta1 +/+ mice but not in TGF-beta1 +/- mice (mice with reduced levels of TGF-beta1). Our study demonstrates that isoflurane organizes several key cytoprotective signaling intermediates including TGF-beta1 receptors, SK1 and ERK, within the caveolae fraction of the plasma membrane. Our findings may help to unravel the cellular signaling pathways of volatile anesthetic-mediated renal protection and lead to new therapeutic applications of inhalational anesthetics during the perioperative period. |
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Authors:
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Joseph H Song; Mihwa Kim; Sang Won Park; Sean W C Chen; Stuart M Pitson; H Thomas Lee |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-01-06 |
Journal Detail:
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Title: American journal of physiology. Renal physiology Volume: 298 ISSN: 1522-1466 ISO Abbreviation: Am. J. Physiol. Renal Physiol. Publication Date: 2010 Apr |
Date Detail:
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Created Date: 2010-03-23 Completed Date: 2010-04-22 Revised Date: 2011-07-27 |
Medline Journal Info:
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Nlm Unique ID: 100901990 Medline TA: Am J Physiol Renal Physiol Country: United States |
Other Details:
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Languages: eng Pagination: F1041-50 Citation Subset: IM |
Affiliation:
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Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, 630 West 168th St., New York, NY 10032-3784, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Caveolae / physiology* Gene Expression Regulation, Enzymologic Humans Isoflurane / pharmacology* Kidney Tubules, Proximal / cytology, metabolism* Mice Phosphotransferases (Alcohol Group Acceptor) / genetics, metabolism* Signal Transduction Transforming Growth Factor beta1 / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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R01-GM-067081/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Transforming Growth Factor beta1; 26675-46-7/Isoflurane; EC 2.7.1.-/Phosphotransferases (Alcohol Group Acceptor); EC 2.7.1.-/sphingosine kinase |
| Comments/Corrections | |
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