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3918 Beneficial Role of Erythrocyte Sphingosine 1-Phosphate in Preventing Renal Macrophage Polarization and Fibrosis through Combating HIF-1α-Dependent Creatine Phosphate Shuttle

Program: Oral and Poster Abstracts
Session: 201. Granulocytes, Monocytes, and Macrophages: Poster III
Hematology Disease Topics & Pathways:
Research, Fundamental Science
Monday, December 11, 2023, 6:00 PM-8:00 PM

Tingting Xie1*, Changhan Chen1*, Yiyan Wang1*, Zhenjiang Li1*, Benjamin C. Brown2*, Rodney E. Kellems3*, Weiru Zhang1*, Angelo D'Alessandro, PhD4 and Yang Xia, MD, PhD1*

1Xiangya Hospital, Central South University, Changsha, China
2Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Denver
3The University of Texas McGovern Medical School at Houston, Houston
4Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO

Introduction: Erythrocytes, the major reservoir and supplier for plasma sphingosine 1 phosphate (S1P), is a potent biolipid signaling via its specific receptors responsible for immune cell trafficking and function. Current evidence has revealed that erythrocyte intracellular S1P has its own function to promote oxygen (O2) delivery to counteract tissue hypoxia.

Aim: To understand whether O2 delivery mediated by erythrocyte S1P is involved in tissue macrophage polarization and fibrosis.

Methods and Results: Genetic ablation of erythrocyte SphK1 (the only enzyme to generate S1P in erythrocyte, eSphK1-/-) resulted in less O2 delivery from erythrocytes, thus leading to severe renal hypoxia, damage and fibrosis in angiotensin II induced hypertensive kidney disease mouse model. Surprisingly, although plasma S1P level was reduced to 50% in Ang II-infused eSphK1-/- mice, these mice displayed preferentially elevated pro-fibrosis M2 macrophages surrounding the hypoxic renal tubules. Surprisingly, there was no significant difference of S1P level in either kidney or renal macrophages between Ang II-infused controls and eSphK1-/- mice, ruling out the possibility of difference of kidney or macrophage S1P levels responsible for renal M2 macrophage polarization. Metabolically, untargeted high-throughput metabolic profiling in macrophages purified from mouse kidney revealed a substantial reduction of amino acids (AAs) and fatty acids (FAs) but increased creatine. We further validate this in vitro by 13C6,15N4-labeled arginine tracer. Hypoxia (1~2% O2) promoted increased 13C2-labeled creatine (arginine downstream metabolite) in murine bone marrow derived macrophages (BMDMs) time dependently. At cellular and molecular level, we further demonstrated that hypoxia signaling via HIF-1a directly enhanced IL-4 induced M2 polarization of BMDMs as well as expression of Ckb (a gene encoding creatine shuttle), which can be reversed by Chrysin (an HIF-1α inhibitor). Preclinical studies revealed that chrysin rescued the severe renal damage in eSphK1-/- mice manipulated with unilateral ureteral obstruction (UUO) and prevented development of chronic kidney disease (CKD) in the control mice. Translational research validated mouse findings in kidney tissue of CKD patients.

Conclusion: Our work has revealed that erythrocyte S1P combats HIF1α-dependent creatine shuttle, renal macrophage polarization and fibrosis and highlighted potential diagnostic and therapeutic possibilities for macrophage polarization and renal fibrosis.

Disclosures: D'Alessandro: Omix Technologies Inc: Current equity holder in private company; Macopharma: Consultancy; Hemanext Inc: Consultancy.

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