| First Author | Schwalm S | Year | 2017 |
| Journal | Am J Pathol | Volume | 187 |
| Issue | 11 | Pages | 2413-2429 |
| PubMed ID | 28807595 | Mgi Jnum | J:248835 |
| Mgi Id | MGI:6094762 | Doi | 10.1016/j.ajpath.2017.06.017 |
| Citation | Schwalm S, et al. (2017) Sphingosine Kinase-2 Deficiency Ameliorates Kidney Fibrosis by Up-Regulating Smad7 in a Mouse Model of Unilateral Ureteral Obstruction. Am J Pathol 187(11):2413-2429 |
| abstractText | 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, alpha-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-beta-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, alpha-smooth muscle actin, CTGF, and PAI-1, but decreased Smad7 expression. SPHK2 plays an important role in kidney fibrogenesis by modulating transforming growth factor-beta signaling. Thus, SPHK2 might be an attractive new target for the treatment of fibrosis in chronic kidney disease. |
