Hypoxia promotes renal damage and the progression of chronic kidney disease (CKD). However, nothing is known about erythrocyte S1P in CKD. This study aimed to investigate the function and metabolic basis of erythrocyte S1P in CKD to explore potential therapeutics. Using erythrocyte-specific SphK1 (sphingosine kinase 1; the only enzyme to produce S1P in erythrocytes) knockout mice (eSphK1−/−) in an experimental model of hypertensive CKD with Ang II (angiotensin II) infusion. 

No prior study has demonstrated the importance of S1P-mediated metabolic reprogramming in erythrocyte function by coupling reduced PP2A activity with increased AMPK1α activity. Thus, these findings are highly innovative and have added a significant new chapter to our understanding of hypertensive CKD’s pathogenesis. These studies are incredibly significant since it sets up a strong foundation for future clinical trials to treat CKD patients. Finally, improving O2 delivery from erythrocytes by targeting our newly identified pathway could help treat other hypoxia conditions beyond CKD.

In conclusion, we demonstrated that S1P (a highly enriched erythrocyte lipid) inhibits PP2A (a highly enriched erythrocyte phosphatase) and in turn results in elevated phosphorylation and activation of AMPK1α (an energy sensor), which activates BPGM (an erythroid-specific enzyme) to reprogram glucose metabolism toward Rapoport-Luebering shunt, promote 2,3-BPG production, and enhance O2 delivery capacity to counteract tissue hypoxia in the setting of hypertensive CKD.

Ref: https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.119.316298