1783-LB: Acute Hyperglycemia Induces Human Podocyte Apoptosis by Increasing Monocyte Release of TNF-α through ER Stress/ROS Activation of ADAM17/iRhom2 Expression

Introduction: Targeting glycemic control based on hemoglobin A1c (A1c) reduces but does not abolish the onset and progression of chronic kidney disease (CKD), suggesting factors other than A1c contribute to the residual risk. Acute hyperglycemia is associated with the development of microalbuminuria, but the underlying mechanisms are unknown. This study aimed to identify if acute hyperglycemia is directly toxic to podocytes or by inducing a proinflammatory monocyte phenotype to cause podocyte apoptosis.

Methods: Monocytes, isolated from healthy subjects, were cultured under euglycemic (5mM) or hyperglycemic (16.7 mM) conditions +/- 10 nM GLP-1 for 6h. QPCR measured monocyte expression of iRhom2 and Adam17, genes responsible for TNF-α release. THP-1 cells, differentiated to macrophages with 160 nM PMA for 48h, were exposed to 5 or 16.7 mM D-glucose for 24h +/- 10 nM GLP-1. Human immortalized podocytes were exposed to 5 or 16.7 mM D-glucose conditioned media from monocytes or THP-1 macrophages for 24h. Caspase 3/7 assessed podocyte apoptosis. TNF-α was tested by ELISA.

Results: Acute hyperglycemia had no direct effect on podocyte apoptosis, but induced a proinflammatory monocyte and THP-1 secretome with high TNF-α release causing podocyte apoptosis. In monocytes, acute hyperglycemia for 6h was sufficient to increase oxidative and ER stress and induce ADAM17/iRhom2 expression, facilitating TNF-α release. Monocyte and THP-1 exposure to GLP-1 prevented acute hyperglycemia induction of ADAM17/iRhom2 expression, TNF-α release, and podocyte apoptosis.

Conclusion: These results show a mechanism by which acute hyperglycemia accelerates the early onset of CKD, and highlights the anti-inflammatory role of GLP-1 independent of glycemic control to reduce CKD progression in diabetes.