Sphingosine kinase 2 cooperating with Fyn promotes kidney fibroblast activation and fibrosis via STAT3 and AKT

Abstract

Sphingosine kinases (Sphks) are the rate-limiting enzymes in the conversion of sphingosine to biologically active sphingosine-1-phosphate. The present study aimed to determine the role of Sphk2 and its downstream targets in renal fibroblast activation and interstitial fibrosis. In the kidney interstitium of patients with renal fibrosis, Sphk2-expressing cells (mainly interstitial fibroblasts) were significantly elevated and highly correlated with disease progression in patients. In a murine model of renal interstitial fibrosis, Sphk2 was upregulated in the kidney of wild-type mice in response to disease progression. Importantly, Sphk2-knockout (KO) mice exhibited significantly lower levels of extracellular matrix (ECM) production and a suppressed inflammatory response in the kidney tissues, compared to those in their wild-type counterparts, whereas the expression of TGF-β1 was unaffected. TGF-β1 effectively upregulated Sphk2 expression in the renal interstitial fibroblast line, NRK-49F, independent of canonical Smad signaling activation. Furthermore, siRNA-mediated Sphk2 knockdown or suppression of Sphk2 activity by ABC294640 exposure effectively attenuated AKT and STAT3 activation and ECM production, but had no effects on Smad2 and Smad3 activation. Sphk2 phosphorylated Fyn to activate downstream STAT3 and AKT, thereby promoting ECM synthesis. Therefore, our findings indicate that targeting Sphk2-Fyn-STAT3/AKT signaling pathway may be a novel therapeutic approach for renal fibrosis.

FYN promotes gastric cancer metastasis by activating STAT3-mediated epithelial-mesenchymal transition

“…FYN (an SRK member) has been reported to interact with STAT3. Researchers have also reported that the FYN-STAT3 axis is crucial in renal and pulmonary fibrosis [ [26] , [27] , [28] ]. The current study confirmed that FYN influenced phospho-STAT3 expression using knockdown and overexpression models.…”

Validation of highly selective sphingosine kinase 2 inhibitors SLM6031434 and HWG-35D as effective anti-fibrotic treatment options in a mouse model of tubulointerstitial fibrosis

“…Previously, we and others have shown that SK2 serves as an attractive novel target to treat renal fibrosis. By using SK2-deficient mice, tubulointerstitial fibrosis, induced by either ureter ligation (UUO) 12,13 or folic acid administration 14 , was reduced as compared to wildtype mice. However, no consensus about the underlying mechanism can be drawn from these different studies.…”

“…More recent studies have started to investigate the role of SK2 in renal pathologies, and have shown that SK2 is expressed in tubuli and in the renal interstitium 12,13 . Our group demonstrated that SK2 protein and activity is strongly upregulated in fibrotic renal tissue.…”

Sphk2−/− mice are protected from obesity and insulin resistance

“…In agreement with our findings, recently published data suggest that Sphk2 and/or S1P are associated with negative health outcomes. Sphk2 has been shown to promote kidney fibrosis via phosphorylation of Fyn to activate STAT3 and AKT, which could not be rescued by addition of extracellular S1P [42]. Increased S1P levels have been recently associated with type 2 diabetes and obesity [21,22].…”