Gαq/11 Signaling Modulates Fibroblast Growth Factor 23 Production and Contributes to Acute Kidney Injury

Fibroblast growth factor 23 (FGF23), primarily secreted by osteocytes and osteoblasts, is essential in regulating phosphate-calcium metabolism by inhibiting renal phosphate reabsorption and vitamin D synthesis. Acute kidney injury (AKI) is characterized by a rapid deterioration in renal function, accompanied by a significant increase in FGF23 levels, which contribute to its severity and progression. This study investigated the mechanistic roles of Gαq and Gα11 proteins, integral components of the lysophosphatidic acid (LPA) signaling pathway, in the regulation of FGF23 expression during AKI. Through targeted knockdown and pharmacological inhibition of Gαq and Gα11 in the osteoblastic MC3T3-E1 and osteocytic MLO-Y4 cells, we demonstrated that individual suppression of these G proteins had minimal impact on both basal and LPA-stimulated FGF23 levels. In contrast, concurrent knockdown significantly diminished FGF23 expression, implicating a synergistic role of Gαq and Gα11 in FGF23 regulation. This hypothesis was supported by using Gαq/11-specific inhibitors, YM-254890 and FR900359, which attenuated LPA-induced FGF23 upregulation. Our findings further elucidated the downstream signaling events, highlighting the involvement of PKC phosphorylation, intracellular calcium mobilization, and the MAPK/ERK1/2 pathway in mediating FGF23 expression. Moreover, in a folic acid-induced AKI mouse model, elevated FGF23 levels in bone, bone marrow, and serum were significantly reduced following YM-254890 administration, underscoring the potential of targeting Gαq/11 signaling in managing AKI-associated FGF23 dysregulation. This study not only advances our understanding of FGF23 regulation in renal injuries but also identifies Gαq/11 signaling modulation as a promising strategy to alleviate AKI severity and other disorders associated with dysregulated FGF23 levels.