Abstract：
:Renal fibrosis is characterized by chronic inflammation and excessive accumulation of extracellular matrix and progressively leads to functional insufficiency and even total loss of kidney function. In this study we investigated the anti-fibrotic potential of two highly selective and potent SK2 inhibitors, SLM6031434 and HWG-35D, in unilateral ureter obstruction (UUO), a model for progressive renal fibrosis, in mice. In both cases, treatment with SLM6031434 or HWG-35D resulted in an attenuated fibrotic response to UUO in comparison to vehicle-treated mice as demonstrated by reduced collagen accumulation and a decreased expression of collagen-1 (Col1), fibronectin-1 (FN-1), connective tissue growth factor (CTGF), and α-smooth muscle actin (α-SMA). Similar to our previous study in Sphk2-/- mice, we found an increased protein expression of Smad7, a negative regulator of the pro-fibrotic TGFβ/Smad signalling cascade, accompanied by a strong accumulation of sphingosine in SK2 inhibitor-treated kidneys. Treatment of primary renal fibroblasts with SLM6031434 or HWG-35D dose-dependently increased Smad7 expression and ameliorated the expression of Col1, FN-1 and CTGF. In summary, these data prove the anti-fibrotic potential of SK2 inhibition in a mouse model of renal fibrosis, thereby validating SK2 as pharmacological target for the treatment of fibrosis in chronic kidney disease.
journal_name
Cell Signaljournal_title
Cellular signallingauthors
Schwalm S,Beyer S,Hafizi R,Trautmann S,Geisslinger G,Adams DR,Pyne S,Pyne N,Schaefer L,Huwiler A,Pfeilschifter Jdoi
10.1016/j.cellsig.2020.109881subject
Has Abstractpub_date
2021-03-01 00:00:00pages
109881eissn
0898-6568issn
1873-3913pii
S0898-6568(20)30358-2journal_volume
79pub_type
杂志文章abstract：:Cortical and medullary thymocytes can be separated from each other by virtue of the fact that only cortical thymocytes bear peanut agglutinin (PNA) receptors. The mitogenic responses of subpopulations of thymocytes were studied. We have confirmed the results of Conlon et al. [(1982) J. Immun. 128, 797-801], that lecti...
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