GPAT2 REGULATES MINERAL METABOLISM IN KIDNEY DISEASE

About This Grant

ABSTRACT: GPAT2 REGULATES MINERAL METABOLISM IN KIDNEY DISEASE Mineral disorder is a common complication of chronic kidney disease and is characterized by increased vascular mineralization and impaired skeletal mineralization—a phenomenon known as the mineralization paradox. This imbalance contributes to cardiovascular and skeletal disease and is a major driver of mortality in patients with chronic kidney disease. Despite its high clinical burden, there are currently no effective therapies to prevent or reverse mineral disorder or to reduce the associated cardiovascular risk. We recently uncovered a novel kidney-driven mechanism in which glycerol-3-phosphate, released from injured renal tissue, stimulates the production of fibroblast growth factor 23 (FGF23). FGF23 is a phosphate-regulating hormone that is also implicated in cardiac hypertrophy and adverse outcomes in chronic kidney disease. This signaling pathway requires glycerol-3-phosphate acyltransferase 2 (GPAT2), a lipid-handling enzyme involved in triglyceride synthesis that determines whether free fatty acids are stored or used for energy metabolism. We hypothesize that reducing GPAT2 activity will shift lipid metabolism, increasing the availability of free fatty acids and decreasing lysophosphatidic acid—a precursor in triglyceride synthesis and a direct stimulator of FGF23. As a result, we expect lower circulating FGF23 levels, reduced cardiovascular stress, and improved phosphate balance, even in the setting of reduced kidney function. Our preliminary data show that patients with advanced chronic kidney disease exhibit elevated GPAT2 expression and decreased free fatty acids. In a mouse model with targeted deletion of Gpat2 in bone-forming cells, we observed increased fatty acid metabolism, reduced FGF23 levels, and surprisingly, a reduction in serum phosphate—suggesting improved phosphate incorporation despite impaired renal clearance. In Aim 1, we will determine whether modulation of GPAT2 can dissociate the harmful effects of elevated FGF23 from the risk of phosphate accumulation by enhancing phosphate utilization in peripheral tissues. We will evaluate systemic mineral metabolism, vascular and cardiac morphology, and the impact of lipid remodeling in both constitutive and inducible Gpat2-deficient mice. We will also investigate the cellular mechanisms by which GPAT2 influences fatty acid metabolism and phosphate handling. In Aim 2, we will test whether either genetic deletion of Gpat2 or pharmacologic inhibition of GPAT activity can prevent or reverse mineral disorder in mouse models of chronic kidney disease. Outcomes will include improvements in vascular calcification, phosphate levels, and cardiac remodeling. If successful, this project will define a kidney-lipid signaling axis as a modifiable driver of phosphate imbalance and cardiovascular disease and may lead to new therapeutic strategies for improving outcomes in patients with chronic kidney disease.