The Calcium Binding Gene Calb1 is an FGF23 target in Distal Convoluted Tubule in Sickle Cell Disease

Grace Z. Xie

Document Type

Article

Publication Date

2025

Keywords

JMG

Abstract

Sickle cell disease (SCD) is a blood disorder characterized by red blood cell sickling and disrupted kidney calcium homeostasis, though the molecular mechanisms underlying calcium handling reprogramming in SCD remain largely unclear. Herein, using single cell transcriptomics and chromatin accessibilities profiling assays, we identify Calb1, a gene encoding a calcium-binding protein CALB1, to be strongly downregulated in SCD mouse models in the distal convoluted tubule cells, suggesting a misregulation of renal calcium handling via CALB1. Motif enrichment and chromatin accessibility analyses suggest that REST (RE1-silencing transcription factor) binds to the Calb1 promoter, acting as a transcriptional repressor. Further, we identify an upstream hormonal dependent pathway via fibroblast growth factor 23 (FGF23) as a potential modulator of REST–Calb1 axis in distal tubule (DT) cells. To support these findings, we examine chronic kidney disease (CKD) and acute kidney injury (AKI) mouse models, both of which show similar patterns of Calb1 repression associated with elevated FGF23. In addition, we reveal a kidney metabolic reprogramming occurring with SCD with a decrease of expression of enzymes involved Embden-Meyerhof-Parnas pathway and the increase of the enzyme BPGM that is associated with the Rapoport-Luebering Shunt pathway. Further, we found through in vitro studies that BPGM metabolite 2,3-diphosphoglycerate (2,3 DPG) impairs FGF23 signaling bioactivity characterized by decrease MAPK signaling-mediated EGR1 expression. Together, our findings highlight a new regulatory network involving FGF23, REST, Calb1, and Bpgm-2,3DPG axis that may contribute to calcium imbalance in SCD.

Please contact the Joan Staats Library for information regarding this document.

COinS