Chronic sphingosine 1-phosphate 1 receptor activation attenuates early-stage diabetic nephropathy independent of lymphocytes.
Chronic sphingosine 1-phosphate 1 receptor activation attenuates early-stage diabetic nephropathy independent of lymphocytes.
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DOI：
10.1038/ki.2010.544
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发表时间：
2011-05
影响因子：
19.6
通讯作者：
Okusa MD
中科院分区：
文献类型：
--
作者：
Awad AS;Rouse MD;Khutsishvili K;Huang L;Bolton WK;Lynch KR;Okusa MD
1 -磷酸鞘氨醇（S1P）是一种多效性脂质介质，它与五种相关的G蛋白偶联受体结合以发挥其作用。由于S1P1受体（S1P1R）的激活可阻断急性肾损伤中的肾脏炎症，我们测试了S1P1R的激活是否能改善大鼠早期糖尿病肾病（DN）中的肾损伤。与对照组相比，溶媒处理的糖尿病大鼠（单次注射链脲佐菌素）在9周时尿白蛋白排泄增加，并伴有肾小管损伤和尿肿瘤坏死因子 -α（TNF -α）增加。这些效应被非选择性的FTY720或选择性S1P1R激动剂SEW2871显著减轻。有趣的是，只有FTY720与总淋巴细胞水平降低有关。在6周后，SEW2871使Rag - 1（T细胞和B细胞缺陷）和野生型糖尿病小鼠的蛋白尿均减少，这表明该效应不依赖于淋巴细胞。另一种受体S1P3R对FTY720介导的保护没有作用，因为糖尿病S1P3R基因敲除小鼠的蛋白尿也减少了。此外，两种激动剂都恢复了WT - 1染色以及足细胞蛋白和肾素mRNA的表达，表明对足细胞有保护作用。这在体外得到了证实，因为SEW2871降低了在高糖培养基中培养的永生化足细胞中TNF -α和血管内皮生长因子mRNA的表达。针对肾脏S1P1R是否将成为糖尿病肾病的一种有用的治疗措施还需要直接的测试。
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.
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影响因子：
4.8
作者：
Brinkmann, V;Davis, MD;Lynch, KR
通讯作者：
Lynch, KR
DOI：
10.1161/01.atv.0000154360.36106.d9
发表时间：
2005-03-01
影响因子：
8.7
作者：
Krump-Konvalinkova, V;Yasuda, S;Siess, W
通讯作者：
Siess, W
DOI：
10.1124/jpet.102.045658
发表时间：
2003-04-01
影响因子：
3.5
作者：
Fujino, M;Funeshima, N;Li, XK
通讯作者：
Li, XK
DOI：
10.1152/ajprenal.00311.2005
发表时间：
2006-06-01
影响因子：
4.2
作者：
Awad, AS;Ye, H;Okusa, MD
通讯作者：
Okusa, MD
影响因子：
3.4
作者：
Kurose, S;Ikeda, E;Mochizuki, M
通讯作者：
Mochizuki, M