Beta-hydroxybutyrate Protects Kidneys through GPR109A Receptor Dependent and Independent Mechanisms

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disorder that leads to chronic kidney disease and is characterized by metabolic dysfunction and inappropriate immune activation. Although our lab has shown that the endogenous metabolite beta-hydroxybutyrate (BHB) reduces cyst growth and replicates the beneficial effects of ketogenic metabolic therapy in animal models of PKD, it remains unclear which of these effects depend on its receptor, GPR109A. This project clarifies the role of BHB as a signaling molecule and determines whether GPR109A mediates BHB’s effects in PKD. To accomplish this, the effects of BHB were tested in both orthologous and non-orthologous PKD models, in the presence and absence of GPR109A. These findings demonstrate that GPR109A signaling is essential for a significant proportion of the therapeutic benefits provided by BHB.