Sphingolipids as potential targets for HUS therapy?

The Hemolytic Uremic Syndrome (HUS) is a severe systemic complication that can occur after an infection with enterohemorrhagic Shiga toxin-producing Escherichia coli. The toxin-induced damage can lead to platelet aggregation and thrombus formation in the arterial microcirculation and subsequently to damage to the renal barriers and further to the development of acute kidney injury.

UKJ researchers from the groups Translational Septomics and Biochemistry of Sepsis have investigated the role of two isoenzymes of sphingosine kinase (SphK1 and 2) in the pathogenesis of HUS. Both SphK catalyze the phosphorylation of sphingosine to sphingosine-1-phosphate (S1P). S1P has been shown to be involved in the maintenance of the endothelial barrier and influences the development and progression of inflammatory kidney diseases. In the mouse model, the researchers were able to demonstrate that repeated application of Shiga toxin in SphK2 knockout (SphK2-/-) mice led to less kidney inflammation and damage compared to wild-type mice, whereas in SphK1-/- mice it led to more severe kidney inflammation and damage. The SphK1-/- and SphK2-/- mice showed an opposite development of sphingolipid levels in kidneys and plasma during HUS development. This finding suggests a potential role of sphingolipid metabolism in the pathogenesis of HUS.

Further studies are required to validate and substantiate the results. However, the identification of sphingolipid metabolism as a potential target for HUS therapy represents a significant advance in the field of HUS research.

Müller T, Krieg N, Lange-Polovinkin AI, Wissuwa B, Gräler MH , Dennhardt S, Coldewey SM (2024) Deletion of Sphingosine Kinase 2 Attenuates Acute Kidney Injury in Mice with Hemolytic-Uremic Syndrome. Int J Mol Sci. 2024 Jul 12;25(14):7683. doi: 10.3390/ijms25147683.