The role of sphingosine-1-phosphate and the therapeutic potential of its signaling pathway in hemolytic-uremic syndrome

• Applicant: Professorin Sina Maren Coldewey, Ph.D.
• Subject Area: Anaesthesiology ; Nephrology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 556179277

The hemolytic uremic syndrome (HUS) can occur as a life-threatening complication of an infection with Shiga toxin (Stx)-producing enterohemorrhagic Escherichia coli. It is clinically defined by a triad of symptoms consisting of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury (AKI). One hallmark of HUS is the impairment of the renal endothelium. To this date, therapy of HUS is restricted to supportive treatment, mainly as the molecular mechanisms of pathogenesis and progression of HUS are not fully understood. It is hypothesized that the primary and crucial event underlying HUS pathology is the Stx-mediated damage of microvascular endothelial cells, which subsequently leads to endothelial barrier dysfunction. The bioactive lipid sphingosine-1-phosphate (S1P) is an important regulator of diverse physiological and pathophysiological processes, including maintenance of endothelial barriers, and influences cellular functions in multiple organs. There is increasing evidence that impaired S1P homeostasis contributes to the development of several conditions associated with an inadequate immune response and/or endothelial barrier dysfunction. Given the multiplicity of cellular processes in which S1P is implicated, the S1P receptor signaling pathway represents a promising avenue for the development of novel therapeutic strategies. Indeed, the pathway can already be pharmacologically modulated by S1P receptor agonists for the treatment of certain diseases. S1P exerts its regulatory function through binding to five distinct S1P receptors. In light of these findings and our own preliminary results, we hypothesize that the S1P signaling axis plays a pivotal role for the maintenance of endothelial barrier function and integrity in HUS. To test our hypothesis, and thereby to evaluate the therapeutic potential of modulating the S1P signaling axis in HUS, we will first investigate Stx-induced endothelial barrier dysfunction in vitro and underlying molecular mechanisms focusing on S1P signaling. Secondly, we evaluate the therapeutic impact of S1P and S1P receptor agonists on Stx-induced endothelial barrier dysfunction and involved molecular mechanisms. Finally, we will assess the effects of promising S1P receptor agonists, selected based on in vitro results, in a well-established murine model of HUS and evaluate their therapeutic potential. The proposed project will make a substantial contribution to the further elucidation of the pathophysiology of HUS and will serve to evaluate the S1P signaling axis as a potential therapeutic target in HUS.

• DFG Programme: Research Grants