title: Sphingosine kinase-1 pathway mediates high glucose-induced fibronectin expression in glomerular mesangial cells.
abstract: Diabetic nephropathy is characterized by accumulation of glomerular extracellular matrix proteins, such as fibronectin (FN). Here, we investigated whether sphingosine kinase (SphK)1 pathway is responsible for the elevated FN expression in diabetic nephropathy. The SphK1 pathway and FN expression were examined in streptozotocin-induced diabetic rat kidney and glomerular mesangial cells (GMC) exposed to high glucose (HG). FN up-regulation was concomitant with activation of the SphK1 pathway as reflected in an increase in the expression and activity of SphK1 and sphingosine 1-phosphate (S1P) production in both diabetic kidney and HG-treated GMC. Overexpression of wild-type SphK1 (SphK(WT)) significantly induced FN expression, whereas treatment with a SphK inhibitor, N,N-dimethylsphingosine, or transfection of SphK1 small interference RNA or dominant-negative SphK1 (SphK(G82D)) abolished HG-induced FN expression. Furthermore, addition of exogenous S1P significantly induced FN expression in GMC with an induction of activator protein 1 (AP-1) activity. Inhibition of AP-1 activity by curcumin attenuated the S1P-induced FN expression. Finally, by inhibiting SphK1 activity, both N,N-dimethylsphingosine and SphK(G82D) markedly attenuated the HG-induced AP-1 activity. Taken together, these results demonstrated that the SphK1 pathway plays a critical role in matrix accumulation in GMC under diabetic condition, suggesting that the SphK1 pathway could be a potential therapeutic target for diabetic nephropathy.
authors: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangdong Pharmaceutical University, Guangzhou 510006, China.
authors: Tian
authors: T
authors: Lan
authors: Weihua
authors: W
authors: Liu
authors: Xi
authors: X
authors: Xie
authors: Suowen
authors: S
authors: Xu
authors: Kaipeng
authors: K
authors: Huang
authors: Jing
authors: J
authors: Peng
authors: Xiaoyan
authors: X
authors: Shen
authors: Peiqing
authors: P
authors: Liu
authors: Lijing
authors: L
authors: Wang
authors: Pu
authors: P
authors: Xia
authors: Heqing
authors: H
authors: Huang
mesh_terms: D000818:Animals; D001786:Blood Glucose; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental; D003928:Diabetic Nephropathies / Q000473:pathology / Q000652:urine; D005109:Extracellular Matrix / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008246:Lysophospholipids / Q000494:pharmacology / Q000502:physiology; D008297:Male; D050527:Mesangial Cells / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D011507:Proteinuria / Q000652:urine; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D001786:Blood Glucose; D005353:Fibronectins; D005947:Glucose; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D017382:Reactive Oxygen Species; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D018808:Transcription Factor AP-1; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate