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

Alaa Awad, Michael D. Rouse, Konstantine Khutsishvili, Liping Huang, W. Kline Bolton, Kevin R. Lynch, Mark D. Okusa

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1090-1098
Number of pages9
JournalKidney International
Volume79
Issue number10
DOIs
StatePublished - Jan 1 2011

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Lysosphingolipid Receptors
Diabetic Nephropathies
Podocytes
Albuminuria
Lymphocytes
Kidney
Tumor Necrosis Factor-alpha
Messenger RNA
Wounds and Injuries
Streptozocin
G-Protein-Coupled Receptors
Acute Kidney Injury
Knockout Mice
Vascular Endothelial Growth Factor A
Albumins
B-Lymphocytes
Staining and Labeling
Inflammation
Lipids
Glucose

All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

Awad, A., Rouse, M. D., Khutsishvili, K., Huang, L., Bolton, W. K., Lynch, K. R., & Okusa, M. D. (2011). Chronic sphingosine 1-phosphate 1 receptor activation attenuates early-stage diabetic nephropathy independent of lymphocytes. Kidney International, 79(10), 1090-1098. https://doi.org/10.1038/ki.2010.544
Awad, Alaa ; Rouse, Michael D. ; Khutsishvili, Konstantine ; Huang, Liping ; Bolton, W. Kline ; Lynch, Kevin R. ; Okusa, Mark D. / Chronic sphingosine 1-phosphate 1 receptor activation attenuates early-stage diabetic nephropathy independent of lymphocytes. In: Kidney International. 2011 ; Vol. 79, No. 10. pp. 1090-1098.
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Awad, A, Rouse, MD, Khutsishvili, K, Huang, L, Bolton, WK, Lynch, KR & Okusa, MD 2011, 'Chronic sphingosine 1-phosphate 1 receptor activation attenuates early-stage diabetic nephropathy independent of lymphocytes', Kidney International, vol. 79, no. 10, pp. 1090-1098. https://doi.org/10.1038/ki.2010.544

Chronic sphingosine 1-phosphate 1 receptor activation attenuates early-stage diabetic nephropathy independent of lymphocytes. / Awad, Alaa; Rouse, Michael D.; Khutsishvili, Konstantine; Huang, Liping; Bolton, W. Kline; Lynch, Kevin R.; Okusa, Mark D.

In: Kidney International, Vol. 79, No. 10, 01.01.2011, p. 1090-1098.

Research output: Contribution to journalArticle

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AU - Awad, Alaa

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