Role of Metabolic Sensor GPR81/HCAR1 in Diabetic Podocytes: Downregulated Lipolysis Results in the Deterioration of Glomerular Filtration Barrier

ABSTRACT The effacement of podocyte foot processes, which form slit diaphragms, are common features of proteinuria. Exploring podocyte energy metabolism, especially under diabetic conditions, may offer insights into the pathogenesis of diabetic kidney disease. Lipid accumulation is recognized as a cause of podocyte cytoskeleton remodeling and insulin resistance. Thus, the role of the metabolic sensor G‐protein‐coupled receptor 81 (GPR81) was examined in the molecular pathway of lipid accumulation in podocytes under hyperglycemic conditions. It was discovered that hyperglycemia downregulated the cyclic adenosine monophosphate/protein kinase A signaling pathway, which downregulated the expression of adipose triglyceride lipase (ATGL). Perilipin 1 was also downregulated; simultaneously, lipid droplet accumulation was enhanced. Glycerol and free fatty acid concentrations were also reduced, providing evidence of lipolysis inhibition. Interestingly, the expression of GPR81 decreased under hyperglycemia conditions despite the evidence of its activation, indicating strict lipolysis regulation. More importantly, cell functions were altered, reflected by an increase in albumin permeability and rearrangement of the actin cytoskeleton. The effect of ATGL activity inhibition on lipolysis, actin cytoskeleton arrangement, and permeability of the podocyte monolayer was investigated. The results were similar to GPR81 downregulation. Altogether, the present data indicate that GPR81 is likely a crucial part of the lipid sensing system, and its alterations during hyperglycemia might contribute to glomerular filtration barrier deterioration in diabetic kidney disease.