Kidney Week

Abstract: TH-PO0215

Phosphate Activates Carbohydrate Responsive Element-Binding Protein via Redox-Dependent Glycerol-3-Phosphate Production

Session Information

• CKD: Mechanisms of Injury and Fibrosis - 1
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2203 CKD (Non-Dialysis): Mechanisms

Authors

• Fan, Yu, Nephrology Division, Department of Medicine, Mass General Brigham, Boston, Massachusetts, United States

Yu Fan, PhD

• Yuan, Yangmian, Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States

Yangmian Yuan, PhD

• Jin, Byungchang, Endocrine Unit, Department of Medicine, Mass General Brigham, Boston, Massachusetts, United States

Byungchang Jin, PhD

• Benede Ubieto, Raquel, Endocrine Unit, Department of Medicine, Mass General Brigham, Boston, Massachusetts, United States

Raquel Benede Ubieto, PhD

• Zhou, Wen, Nephrology Division, Department of Medicine, Mass General Brigham, Boston, Massachusetts, United States

Wen Zhou, PhD

• Simic, Petra, Nephrology Division, Department of Medicine, Mass General Brigham, Boston, Massachusetts, United States

Petra Simic, MD, PhD

• Goodman, Russell, Endocrine Unit, Department of Medicine, Mass General Brigham, Boston, Massachusetts, United States

Russell Goodman, MD, PhD

• Rhee, Eugene P., Nephrology Division, Department of Medicine, Mass General Brigham, Boston, Massachusetts, United States

Eugene P. Rhee, MD, FASN

Background

Inorganic phosphate (Pi) is essential for bone mineralization, cell signaling, generation of high-energy phosphate esters, and as a component of DNA and membrane lipids. Recent work has elucidated a mechanism for Pi sensing in the kidney proximal tubule, whereby Pi-stimulated glycolysis reduces cytosolic NAD+/NADH, thereby stimulating the production of glycerol-3-phosphate (G-3-P). Recent work by other groups has shown that G-3-P is a direct ligand activator of the transcription factor carbohydrate-responsive element-binding protein (ChREBP) in the liver, a key regulator of metabolic gene expression. Whether Pi-stimulated G-3-P production in the kidney activates ChREBP is unknown.

Methods

We examined the effect of Pi on cytosolic redox state, G-3-P production, and ChREBP activation in opossum kidney (OK) and primary mouse/human proximal tubule cells. Cytosolic NAD+/NADH ratio was measured with SoNAR sensor, G-3-P by LC-MS, ChREBP activity by ChoRE-luciferase reporter, and nuclear localization by immunofluorescence. Pharmacologic inhibition of phosphate transport (NPT2a inhibitor) and glycolysis (2-DG), together with genetic manipulation of cytosolic redox state using enzymatic tools (LbNOX and EcSTH), were used to examine this pathway. To evaluate in vivo effects, we used ChREBP knockout mice (Six2-Cre) and controls under high-phosphate and adenine diet-induced CKD conditions.

Results

Pi exposure reduced the cytosolic NAD+/NADH ratio in proximal tubule cells, consistent with enhanced glycolytic flux, and increased G-3-P production. Lowering NAD+/NADH increased, whereas increasing NAD+/NADH suppressed, G-3-P production and ChREBP activity. Pi induced nuclear accumulation and activation of ChREBP, which was abolished by inhibition of phosphate uptake or glycolysis and rescued by exogenous G-3-P. Consistent with these findings, G-3-P levels and ChREBP activity were increased in vivo under high-phosphate and CKD conditions. Functionally, nephron-specific ChREBP deletion attenuated kidney injury in the adenine-induced CKD model, as evidenced by improved renal function and reduced markers of inflammation and fibrosis.

Conclusion

These findings outline a novel Pi–cytosolic NAD+/NADH–G-3-P–ChREBP signaling axis in the proximal tubule. More work is required to define the transcriptional program downstream of Pi sensing, in health and in disease, and to determine how this signaling axis may contribute to kidney injury.

Funding

• Other NIH Support