P2Y receptor-mediated regulation of lipolysis, lipid droplet dynamics, and energy metabolism in podocytes

Abstract Abnormal lipid metabolism that results in excessive lipid accumulation in the kidney is closely associated with the pathogenesis of glomerulopathies. Podocytes cover the external surface of glomerular capillaries and are known to be particularly sensitive to lipid overload. Lipids accumulate in lipid droplets, specialized organelles that store neutral lipids. Lipid droplets regulate the mobilization of free fatty acids (FFAs) through lipolysis, coordinated by complex machinery, including adipose triglyceride lipase and perilipins. Moreover, activation of the lipolytic cascade leads to the release of stored energy in the form of FFAs, which serve as substrates for subsequent mitochondrial oxidation. Because cyclic adenosine monophosphate, a key second messenger downstream of purinergic P2Y receptors, governs lipolysis, we investigated whether P2Y signaling modulates podocyte lipid metabolism and bioenergetics. Primary rat podocytes were stimulated with uridine-5’-triphosphate and selective P2Y₁ and P2Y₄ receptor agonists. P2Y activation suppressed lipolysis, reflected by alterations of lipolytic protein levels, lower FFA levels, and changes in lipid droplet morphology and distribution. Lower FFA availability was accompanied by a decrease in oxidative phosphorylation and a compensatory increase in glycolysis. Altogether, these findings highlight a significant role for P2Y signaling in overall podocyte metabolism through the regulation of lipid metabolism. Targeting purinergic signaling to control lipolysis may be a therapeutic strategy to mitigate lipid-driven podocyte injury and glomerular dysfunction.