Logic-Based Modeling of Inflammatory Macrophage Crosstalk with Glomerular Endothelial Cells in Diabetic Kidney Disease

Diabetic kidney disease is a complication in 1 out of 3 patients with diabetes. Aberrant glucose metabolism in diabetes leads to an immune response causing inflammation and to structural and functional damage in the glomerular cells of the kidney. Complex cellular signaling lies at the core of metabolic and functional derangement. Unfortunately, the mechanism underlying the role of inflammation in glomerular endothelial cell dysfunction during diabetic kidney disease is not fully understood. Computational models in systems biology allow the integration of experimental evidence and cellular signaling networks to understand mechanisms involved in disease progression. We built a logic-based ordinary differential equations model to study macrophage-dependent inflammation in glomerular endothelial cells during diabetic kidney disease progression. We studied the crosstalk between macrophages and glomerular endothelial cells in the kidney using a protein signaling network stimulated with glucose and lipopolysaccharide. The network and model were built using the open-source software package Netflux. This modeling approach overcomes the complexity of studying network models and the need for extensive mechanistic details. The model simulations were fitted and validated against available biochemical data from in vitro experiments. The model identified mechanisms responsible for dysregulated signaling in macrophages and glomerular endothelial cells during diabetic kidney disease. In addition, we investigated the influence of signaling interactions and species that on glomerular endothelial cell morphology through selective knockdown and downregulation. We found that partial knockdown of VEGF receptor 1, PLC-γ, adherens junction proteins, and calcium partially recovered the endothelial cell fenestration size. Our model findings contribute to understanding signaling and molecular perturbations that affect the glomerular endothelial cells in the early stage of diabetic kidney disease.