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Am J Pathol. 2017 Nov;187(11):2413-2429. doi: 10.1016/j.ajpath.2017.06.017. Epub 2017 Aug 12.

Sphingosine Kinase-2 Deficiency Ameliorates Kidney Fibrosis by Up-Regulating Smad7 in a Mouse Model of Unilateral Ureteral Obstruction.

Author information

1
Institutes of General Pharmacology and Toxicology, Pharmazentrum Frankfurt, University Hospital of Goethe University Frankfurt, Frankfurt am Main, Germany. Electronic address: s.schwalm@med.uni-frankfurt.de.
2
Institutes of General Pharmacology and Toxicology, Pharmazentrum Frankfurt, University Hospital of Goethe University Frankfurt, Frankfurt am Main, Germany.
3
Clinical Pharmacology, Pharmazentrum Frankfurt, University Hospital of Goethe University Frankfurt, Frankfurt am Main, Germany.
4
Institute of Pharmacology and Toxicology, University of Bern, Inselspital INO-F, Bern, Switzerland.

Abstract

Kidney fibrosis is a hallmark of chronic kidney disease and leads to extracellular matrix accumulation, organ scarring, and loss of kidney function. In this study, we investigated the role of sphingosine kinase-2 (SPHK2) on the progression of tubular fibrosis by using a mouse unilateral ureteral obstruction (UUO) model. We found that SPHK2 protein and activity are up-regulated in fibrotic renal tissue. Functionally, Sphk2-deficient (Sphk2-/-) mice showed an attenuated fibrotic response to UUO compared with wild-type mice, as demonstrated by reduced collagen abundance and decreased expression of fibronectin-1, collagen I, α-smooth muscle actin, connective tissue growth factor (CTGF), and plasminogen activator inhibitor (PAI-1). More important, these changes were associated with increased expression of the antifibrotic protein Smad7 and higher levels of sphingosine in Sphk2-/- UUO kidneys. Mechanistically, sphingosine ameliorates transforming growth factor-β-induced collagen accumulation, CTGF, and PAI-1 expression, but enhances Smad7 protein expression in primary kidney fibroblasts. In a complementary approach, in human Sphk2-overexpressing mice, UUO resulted in exacerbated signs of fibrosis with increased collagen accumulation, higher expression levels of fibronectin-1, collagen I, α-smooth muscle actin, CTGF, and PAI-1, but decreased Smad7 expression. SPHK2 plays an important role in kidney fibrogenesis by modulating transforming growth factor-β signaling. Thus, SPHK2 might be an attractive new target for the treatment of fibrosis in chronic kidney disease.

PMID:
28807595
DOI:
10.1016/j.ajpath.2017.06.017
[Indexed for MEDLINE]

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