NDLI: Chronic sphingosine 1-phosphate 1 receptor activation attenuates early-stage diabetic nephropathy independent of lymphocytes

Content Provider	PubMed Central
Author	Awad, Alaa S. Rouse, Michael D. Khutsishvili, Konstantine Huang, Liping Bolton, W. Kline Lynch, Kevin R. Okusa, Mark D.
Copyright Year	2011
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.
Related Links	http://dx.doi.org/10.1038/ki.2010.544
Ending Page	1098
Page Count	9
Starting Page	1090
File Format	PDF
ISSN	00852538
e-ISSN	15231755
Journal	Kidney international
Issue Number	10
Volume Number	79
Language	English
Publisher Date	2011-05-01
Access Restriction	Open
Subject Keyword	Nephrology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Nephrology

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