# Multi-cellular network model predicts alterations in glomerular endothelial structure in diabetic kidney disease

## TL;DR

A computational model predicts how high blood sugar affects kidney cell structure in diabetes, suggesting new treatment targets.

## Contribution

A multi-cellular network model was developed to predict glomerular endothelial structure alterations in diabetic kidney disease.

## Key findings

- Hyperglycemia leads to significant fenestration loss and increased fenestration size in glomerular endothelial cells.
- Glycemic control is less effective as diabetic kidney disease progresses.
- Targeting Rho-associated kinase, VEGF-A, NFκB, and actin stress fibers could maintain fenestration integrity.

## Abstract

The progression of diabetic kidney disease is often characterized by early dysfunction of glomerular endothelial cells, including alterations in fenestration size and number linked to impaired glomerular filtration. However, the cellular mechanisms regulating fenestrations in glomerular endothelial cells 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 glomerular endothelial cells. Key drivers of fenestration loss and size changes were identified by incorporating signaling pathways related to actin remodeling, myosin light chain kinase, Rho-associated kinase, calcium, and VEGF and its receptors. The model predicted how hyperglycemia in diabetic mice leads to significant fenestration loss and increased size of fenestrations. Glycemic control in the pre-diabetic stage mitigated signaling dysregulation but was less effective as diabetic kidney disease developed and progressed. The model suggested alternative disease intervention strategies to maintain the integrity of the fenestration structure, such as targeting Rho-associated kinase, VEGF-A, NFκB, and actin stress fibers.

Diabetic kidney disease is a serious complication of diabetes that affects approximately 20–40% of diabetic patients and can lead to kidney failure. Early diagnosis and treatment of diabetic kidney disease are critical in slowing the progression of the disease and preventing kidney failure. The progression of diabetic kidney disease is often characterized by structural changes in glomerular endothelial cells, which are important cells in the kidney zones responsible for filtration. In this work, we expanded our previous model of chemical interactions in glomerular endothelial cells that focused on cell culture data from experiments outside an organism. Here, the model is adapted to data from mice. Using a protein-protein interaction network, we computationally examined key pathways that relate hyperglycemia in diabetic mice to significant structural changes in glomerular endothelial cells. The analysis identified that targeting specific pathways and proteins could maintain structural integrity when glucose control alone is insufficient. The proposed disease targets and biomarkers are closely correlated with structural changes in glomerular endothelial cells and could support improved kidney function and disease management.