A Multi-Cellular Network Model Predicts Changes in Glomerular Endothelial Structure in Diabetic Kidney Disease

AshleeFord Versypt

University at Buffalo, The State University of New York

"A Multi-Cellular Network Model Predicts Changes in Glomerular Endothelial Structure in Diabetic Kidney Disease"

Diabetic kidney disease (DKD) progression is often marked by early glomerular endothelial cell (GEC) dysfunction, including alterations in the fenestration size and number linked to impaired glomerular filtration. However, the cellular mechanisms regulating GEC fenestrations remain poorly understood due to limitations in existing in vitro models, challenges in imaging small fenestrations in vivo, and inconsistencies between in vitro and in vivo findings. This study used a logic-based protein-protein interaction network model with normalized Hill functions for dynamics to explore how glucose-mediated signaling dysregulation impacts fenestration dynamics in GECs. We identified key drivers of fenestration loss and size changes by incorporating signaling pathways related to actin remodeling, myosin light chain kinase, Rho-associated kinase, calcium, and VEGF and its receptor. The model predicted how hyperglycemia in diabetic mice leads to significant fenestration loss and increased size of fenestrations. We found that glycemic control in the pre-DKD stage mitigated signaling dysregulation but was less effective as DKD developed and progressed. The model suggested alternative disease intervention strategies to maintain fenestration structure integrity, such as targeting Rho-associated kinase, VEGF-A, NFκB, and actin stress fibers.
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