Abstract: FR-PO351
Erythrocyte Sphk1 Activation Coupled with PP2A Inhibition: A Missing Component to Counteract CKD
Session Information
- CKD: Mechanisms - II
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Xie, Tingting, University of Texas Health Science Center at Houston, Houston, Texas, United States
- Zhang, Weiru, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Peng, Zhangzhe, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Song, Anren, University of Texas Health Science Center at Houston, Houston, Texas, United States
- Xia, Yang, University of Texas Health Science Center at Houston, Houston, Texas, United States
Group or Team Name
- Dr. Angelo D'Alessandro's group
Background
Hypoxia drives chronic kidney diseases (CKD) and promotes end organ damage. The erythrocyte is the only cell type delivering oxygen (O2) and O2 releasing capacity is finely regulated by hypoxia. However, its role and regulatory mechanisms in CKD remain unknown.
Methods
Untargeted metabolomics screening in the plasma and erythrocyte of mice infused with or without angiotensin II (Ang II) at 500ng/kg/min up to 14 days was conducted. Mice with specific ablation of Sphk1 in erythrocytes and patients with CKD were used to determine its function in CKD, potential mechanisms and human relevance.
Results
Genetic depletion of erythrocyte specific Sphingosine Kinase 1 (Sphk1, the only enzyme to generate S1P in erythrocytes) leads to severe renal hypoxia, persistently active HIF-1a, sustained inflammation, imbalanced vasoactive factors and fibrosis comparing to the Ang II-infused controls. Mechanistically, using untargeted erythrocyte metabolic profiling, we found that Ang II-infused controls but not erythrocyte Sphk1 knockout mice show highly active glycolysis, which fuels erythrocyte energy supply and O2 release mediator. These studies led us further discover that Sphk1 activation induces AMPK-mediated activation of BPG mutase and thus the production of 2,3-biphosphoglycerate (2,3-BPG), an erythrocyte specific glycolysis metabolite negatively regulating hemoglobin-O2 binding affinity and eventually triggers O2 delivery to the kidney. Furthermore, we then provide both pharmacological and genetic evidence that AMPK phosphorylation and activation of BPGM in erythrocytes, is regulated by sphingolipid mediated protein phosphatase 2A (PP2A) inhibition. Finally, human translational studies validated mouse findings that erythrocyte BPG mutase and Sphk1 activity were significantly induced in the erythrocytes of CKD patients compared to normal controls and their elevations were correlated to disease severity.
Conclusion
Overall, our study elucidates that erythrocyte Sphk1 activation induced S1P production promotes 2,3-BPG production and O2 delivery via a PP2A-AMPK-dependent signaling cascade to counteract CKD. These findings add a significant molecular new insight to CKD and immediately suggest new therapeutic avenues.
Funding
- Other NIH Support