Sphingosine kinase 1 protects renal tubular epithelial cells from renal fibrosis via induction of autophagy |
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| Affiliation: | 1. Department of Pathology, Hebei Medical University, Shijiazhuang, China;2. Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China;3. Department of Ophthalmology, Second Hospital, Hebei Medical University, Shijiazhuang, China;4. Department of Foreign Languages, Hebei Medical University, Shijiazhuang, China;1. Tongji University School of Medicine, Shanghai 200092, China;2. Department of Cardiology, Zhoupu Hospital, Shanghai 201318, China;1. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA;2. Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA;3. Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA;4. Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands;5. Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA;6. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA;7. Nephrology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA;8. Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA;9. Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94143, USA;10. California Institute for Quantitative Biosciences, San Francisco, CA 94158, USA;11. Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94143, USA;1. Department of Tumor Biology (Cancer Research Institute), Seoul National University College of Medicine, Seoul 03080, South Korea;2. Department of Forensic Medicine, National Forensic Service Busan Institute, Yangsan 50612, South Korea;3. Department of Pathology, Seoul National University College of Medicine, Seoul 03080, South Korea;4. Department of Pathology, Eulji University Hospital, Eulji University School of Medicine, Daejeon 35233, South Korea;5. Department of Pathology, Jeju National University Hospital, Jeju 63241, South Korea;6. Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 22212, South Korea;7. Department of Anatomy, Seoul National University College of Medicine, Seoul 03080, South Korea;8. Ischemic/Hypoxic Disease Institute Medical Research Center, Seoul National University College of Medicine, Seoul 03080, South Korea |
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| Abstract: | Autophagy is an important homoeostatic mechanism for the lysosomal degradation of protein aggregates and damaged cytoplasmic components. Recent studies suggest that autophagy which is induced by TGF-β1 suppresses kidney fibrosis in renal tubular epithelial cells (RTECs) of obstructed kidneys. Sphingosine kinase 1(SK1), converting sphingosine into endogenous sphingosine-1-phosphate (S1P), was shown to modulate autophagy and involved in the processes of fibrotic diseases. Since SK1 activity is also up-regulated by TGF-β1, we explored its effect on the induction of autophagy and development of renal fibrosis in this study. In vitro, SK1 expression and activity were markedly increased by TGF-β1 stimulation in a time and concentration dependent manner, and concomitant changes in autophagic response were observed in HK-2 cells. Further, knockdown of SK-1 led to a decrease of autophagy whereas overexpression of SK1 caused a greater induction of autophagy. In addition, overexpression of SK1 resulted in decreased of mature TGF-β levels through autophagic degradation. In vivo, SK1 enzymatic activity and autophagic response were both up-regulated in a mouse model of kidney fibrosis induced by unilateral ureteral obstruction (UUO); meanwhile, increased of mature TGF-β1 and deposition of extracellular matrix (ECM) were observed in tubulointerstitial areas compared with sham-operated mice. However, aggravation of renal fibrosis was detected when SK1 inhibitor PF-543 was applied to suppress SK1 enzymatic activity in UUO mice. At the same time, autophagy was also inhibited by PF-543. Thus, our findings suggest that SK1 activation is renoprotective via induction of autophagy in the fibrotic process. |
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| Keywords: | Autophagy Fibrosis Kidney Sphingosine kinase-1 Transforming growth factor-b1 |
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