title: Chronic sphingosine 1-phosphate 1 receptor activation attenuates early-stage diabetic nephropathy independent of lymphocytes.
abstract: Sphingosine 1-phosphate (S1P), a pleiotropic lipid mediator, binds to five related G-protein-coupled receptors to exert its effects. As S1P1 receptor (S1P1R) activation blocks kidney inflammation in acute renal injury, we tested whether activation of S1P1Rs ameliorates renal injury in early-stage diabetic nephropathy (DN) in rats. Urinary albumin excretion increased in vehicle-treated diabetic rats (single injection of streptozotocin), compared with controls, and was associated with tubule injury and increased urinary tumor necrosis factor-α (TNF-α) at 9 weeks. These effects were significantly reduced by FTY720, a non-selective, or SEW2871, a selective S1P1R agonist. Interestingly, only FTY720 was associated with reduced total lymphocyte levels. Albuminuria was reduced by SEW2871 in both Rag-1 (T- and B-cell deficient) and wild-type diabetic mice after 6 weeks, suggesting that the effect was independent of lymphocytes. Another receptor, S1P3R, did not contribute to the FTY720-mediated protection, as albuminuria was also reduced in diabetic S1P3R knockout mice. Further, both agonists restored WT-1 staining along with podocin and nephrin mRNA expression, suggesting podocyte protection. This was corroborated in vitro, as SEW2871 reduced TNF-α and vascular endothelial growth factor mRNA expression in immortalized podocytes grown in media containing high glucose. Whether targeting kidney S1P1Rs will be a useful therapeutic measure in DN will need direct testing.
authors.affiliation: Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Alaa S
authors.initials: AS
authors.lastname: Awad
authors.forename: Michael D
authors.initials: MD
authors.lastname: Rouse
authors.forename: Konstantine
authors.initials: K
authors.lastname: Khutsishvili
authors.forename: Liping
authors.initials: L
authors.lastname: Huang
authors.forename: W Kline
authors.initials: WK
authors.lastname: Bolton
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Lynch
authors.forename: Mark D
authors.initials: MD
authors.lastname: Okusa
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D000068876:Fingolimod Hydrochloride; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008214:Lymphocytes / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010069:Oxadiazoles / Q000494:pharmacology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D050199:Podocytes / Q000378:metabolism; D011409:Propylene Glycols / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D049349:Receptors, Lysosphingolipid / Q000819:agonists / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000652:urine; D000099157:Sphingosine Kinase
chemical_list: D000068876:Fingolimod Hydrochloride; D010069:Oxadiazoles; D017853:Phosphotransferases (Alcohol Group Acceptor); D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D013876:Thiophenes; D014409:Tumor Necrosis Factor-alpha; D000099157:Sphingosine Kinase; C503964:SEW2871