Journal Article Research Support, N.I.H., Extramural Ppublish 3 citations
PubMed: 38820589 DOI: 10.1182/blood.2023023528
Heme-induced loss of renovascular endothelial protein C receptor promotes chronic kidney disease in sickle mice.
Blood 144(5):552-564
Authors: Qiyang Chen, Rimi Hazra, Danielle Crosby, Diane Lenhart, Shane C Lenhart, Paritosh Mondal, Yingze Zhang, Seyed M Nouraie, Roderick J Tan, Charles T Esmon, L Vijay Mohan Rao, Kang Kim, Samit Ghosh
Affiliations
- Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA.
- Department of Medicine, Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA.
- Department of Medicine, Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA. Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA.
- Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA.
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, PA.
- Coagulation Biology Laboratory, Oklahoma Medical Research Foundation, Oklahoma City, OK.
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX.
- Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA. Department of Medicine, Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA. Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA.
Abstract
Chronic kidney disease (CKD) is a major contributor to morbidity and mortality in sickle cell disease (SCD). Anemia, induced by chronic persistent hemolysis, is associated with the progressive deterioration of renal health, resulting in CKD. Moreover, patients with SCD experience acute kidney injury (AKI), a risk factor for CKD, often during vaso-occlusive crisis associated with acute intravascular hemolysis. However, the mechanisms of hemolysis-driven pathogenesis of the AKI-to-CKD transition in SCD remain elusive. Here, we investigated the role of increased renovascular rarefaction and the resulting substantial loss of the vascular endothelial protein C receptor (EPCR) in the progressive deterioration of renal function in transgenic SCD mice. Multiple hemolytic events raised circulating levels of soluble EPCR (sEPCR), indicating loss of EPCR from the cell surface. Using bone marrow transplantation and super-resolution ultrasound imaging, we demonstrated that SCD mice overexpressing EPCR were protective against heme-induced CKD development. In a cohort of patients with SCD, plasma sEPCR was significantly higher in individuals with CKD than in those without CKD. This study concludes that multiple hemolytic events may trigger CKD in SCD through the gradual loss of renovascular EPCR. Thus, the restoration of EPCR may be a therapeutic target, and plasma sEPCR can be developed as a prognostic marker for sickle CKD.
MeSH
Kidney Diseases, Cells, Hematology, Endothelial Protein C Receptor, Kidney, Heme, Hemolysis, Protein C, Plasma