title: Curcumin ameliorates diabetic nephropathy by inhibiting the activation of the SphK1-S1P signaling pathway.
abstract: Curcumin, a major polyphenol from the golden spice Curcuma longa commonly known as turmeric, has been recently discovered to have renoprotective effects on diabetic nephropathy (DN). However, the mechanisms underlying these effects remain unclear. We previously demonstrated that the sphingosine kinase 1-sphingosine 1-phosphate (SphK1-S1P) signaling pathway plays a pivotal role in the pathogenesis of DN. This study aims to investigate whether the renoprotective effects of curcumin on DN are associated with its inhibitory effects on the SphK1-S1P signaling pathway. Our results demonstrated that the expression and activity of SphK1 and the production of S1P were significantly down-regulated by curcumin in diabetic rat kidneys and glomerular mesangial cells (GMCs) exposed to high glucose (HG). Simultaneously, SphK1-S1P-mediated fibronectin (FN) and transforming growth factor-beta 1 (TGF-β1) overproduction were inhibited. In addition, curcumin dose dependently reduced SphK1 expression and activity in GMCs transfected with SphK(WT) and significantly suppressed the increase in SphK1-mediated FN levels. Furthermore, curcumin inhibited the DNA-binding activity of activator protein 1 (AP-1), and c-Jun small interference RNA (c-Jun-siRNA) reversed the HG-induced up-regulation of SphK1. These findings suggested that down-regulation of the SphK1-S1P pathway is probably a novel mechanism by which curcumin improves the progression of DN. Inhibiting AP-1 activation is one of the therapeutic targets of curcumin to modulate the SphK1-S1P signaling pathway, thereby preventing diabetic renal fibrosis.
authors.affiliation: Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Huang
authors.forename: Kaipeng
authors.initials: K
authors.lastname: Huang
authors.forename: Tian
authors.initials: T
authors.lastname: Lan
authors.forename: Xi
authors.initials: X
authors.lastname: Xie
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Shen
authors.forename: Peiqing
authors.initials: P
authors.lastname: Liu
authors.forename: Heqing
authors.initials: H
authors.lastname: Huang
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002478:Cells, Cultured; D003474:Curcumin / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy*; D003928:Diabetic Nephropathies / Q000201:enzymology / Q000517:prevention & control*; D004353:Drug Evaluation, Preclinical; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D000975:Antioxidants; D003474:Curcumin; D005353:Fibronectins; D005947:Glucose; D048031:JNK Mitogen-Activated Protein Kinases; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D018808:Transcription Factor AP-1; D053773:Transforming Growth Factor beta1; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate