The role of sphingosine-1phosphate in chronic kidney disease

• 1. The mechanism of HIF-2 α stabilization by iS1P

• In contrast to the vast knowledge about the S1P receptor-mediated functions of eS1P, much less is known about the effects of the iS1P in renal fibrosis and renal anemia. Our group has previously shown that eS1P stimulates Epo synthesis in mouse renal interstitial fibroblasts by S1PR1 and 3 activation and HIF-2α stabilization 34502385. Additionally, our group has also shown that iS1P has different effects on Epo secretion depending on the subcellular S1P sites of production. 35682566. We therefore hypothesise that the inhibition the S1P-degrading enzyme SPL and the overexpression of Sphk2 lead to an increase of iS1P, which further affects the Epo production. In this thesis, I aim to unravel the mechanism through which the iS1P stabilizes HIF-2α and leads to an increased Epo production.

•

• 2. Effect of iS1P on the fibrotic response to TGF-β

• Previous work from our group in human podocytes showed that upregulation of SphK1 and iS1P production mediates a protective effect on TGF-stimulated CTGF expression and that a SphK1 inhibitor accelerates a fibrotic response 19657322 . Moreover, in a mouse model of kidney fibrosis our group and others have shown that that SphK2-/- mice were partially protected from interstitial fibrosis. Thus, we hypothesize that SphK2 overexpression enhances the fibrotic response and should down-regulate Epo synthesis We aim to confirm this hypothesis and to unravel the molecular mechanisms of this augmented fibrotic response.