The Receptor GPR109A Modifies Cystic Disease Progression and the Effect of Beta-Hydroxybutyrate in Polycystic Kidney Disease

Background: Our lab's research has demonstrated that ketogenic metabolic therapies (KMT) can effectively slow and reverse the progression of polycystic kidney disease (PKD) in multiple rodent models of the disease. Moreover, we have discovered that the beneficial effects of KMT are largely mediated by the action of the metabolite beta-hydroxybutyrate (BHB). This finding opens up the possibility of developing BHB supplementation as a potential treatment for PKD. In addition to its role as an energy substrate, BHB acts as a signaling molecule and binds to the receptor GPR109A. GPR109A is expressed on macrophages and epithelial cells, regulating the activity of adenylate cyclase, a known contributor to PKD progression. Given the integral role GPR109A plays in cellular signaling, it is strongly implicated in mediating the effect of KMT in PKD, highlighting its potential as a therapeutic target. Methods: Three-week-old Pkd1RC/RC mice with and without concurrent Gpr109a gene inactivation were treated with BHB until 3 months of age and then euthanized for analysis. Additionally, 4-week-old Pkd1:Nestin-Cre mice with and without Gpr109a were treated with a ketogenic diet for 4 weeks and then euthanized for analysis. Results: Loss of GPR109A causes a worsening of cystic disease progression in the Nestin-Cre mouse, altering the effect of a ketogenic diet on PKD. Additionally, GPR109A Knockout in the Pkd1RC/RC mouse caused a loss of some of the beneficial effects of BHB supplementation. Conclusion: We found that loss of GPR109A caused a worsening of disease in the Nestin:Cre mouse and a partial loss of BHB's effect in the Pkd1RC/RC mouse. These results indicate that GPR109A is at least partially involved in slowing the progression of PKD, regulating the endogenous action of BHB as well as the beneficial effect of KMT on PKD progression. Funding: NIDDK Support