In patients with chronic kidney disease, impaired phosphate clearance leads to high serum levels of the phosphaturic hormone fibroblast growth factor 23 (FGF23). Elevated FGF23 is also associated with an increased risk of acute kidney injury (AKI) and worse outcomes in AKI survivors. A new study by Eugene Rhee and colleagues suggests that kidney-derived glycerol 3-phosphate (G3P) induces FGF23 production in bone.

The researchers measured proteins and metabolites in aortic and renal venous samples from 17 individuals and found that G3P was the only molecule that correlated significantly with arterial levels of FGF23; this correlation was stronger than that between arterial phosphate and FGF23 levels. Renal venous α-Klotho did not correlate with either renal venous G3P or arterial FGF23.

In mice, a single injection of G3P increased plasma FGF23 levels, which was associated with a rise in urinary phosphate and a decrease in plasma calcitriol but had no effect on parathyroid hormone levels. The researchers then investigated a potential role for lysophosphatidic acid (LPA), which is synthesized by G3P acyltransferase (GPAT), downstream of G3P. Injection of G3P increased LPA levels in bone but not in plasma and this effect was blocked by a GPAT inhibitor. Plasma FGF23 levels also increased in response to LPA injection, but only in mice with intact Lpar1, which encodes the most highly expressed LPA receptor in bone.

Using bilateral ischaemia–reperfusion injury (IRI) as a mouse model of AKI, the researchers showed that IRI significantly increased kidney and plasma G3P levels compared with controls; this rise was LPAR1-dependent and was blunted in the presence of a GPAT inhibitor. Following cardiac surgery, plasma G3P levels were also significantly higher in patients who subsequently developed AKI than in those who did not.

“G3P released by the kidney stimulates bone production of FGF23 via local conversion of G3P to LPA and binding to LPAR1 — these results may highlight a new kidney endocrine function,” concludes Rhee. “We plan to investigate whether inhibition of this G3P–FGF23 axis is beneficial in AKI.”