(516g) Collagen Deposition during Diabetic Kidney Disease Enhances Cellular Communication

Diabetes is a significant burden on public health in the U.S. and worldwide. In the year 2015, over 400 million people were diagnosed with diabetes worldwide—a number that is expected to rise to over 600 million by the year 2040 [1]. One-third of these diabetic patients are expected to develop diabetic kidney disease, the leading cause of kidney failure [1]. Our lack of understanding of how diabetic kidney disease progresses and affects cellular and tissue function has contributed to our inability to mitigate the rapidly rising burden of diabetic kidney disease. Diabetic kidney disease, characterized by proteinuria and a loss in glomerular filtration rate, is induced by biochemical perturbations and morphological changes such as excess collagen deposition in the kidney. Although excess collagen deposition is a hallmark of diabetic kidney damage, its impact on cellular and tissue function is still not well understood. Thus, our aim is to use a modeling approach to fill this gap in knowledge.

Collagen deposition occurs in the mesangium, a tissue located at the center of the filtration unit of the kidney, the glomerulus. The mesangium is composed of a collagenous matrix and is the region that separates the three key glomerular cells: mesangial, endothelial and podocyte cells. Studies have shown that these three cell types are in constant communication and that interference in this communication can lead to dysfunction within the glomerulus [2,3]. During diabetic kidney damage, the collagen deposition that occurs in the mesangium changes the transport property of the matrix, and, therefore, the ability of signaling molecules to traverse through that medium. The extent to which collagen deposition impacts the ability of glomerular cells to communicate has not been previously investigated. Using an analytical model for intercellular signaling and transport combined with a theoretical correlation for diffusion coefficients in fibrous biomaterials, we investigated whether collagen deposition impacts glomerular cell communication. We hypothesized that the pathological deposition of collagen decreases the ability of glomerular cells to communicate.

Our model predicted that collagen deposition enhances the signaling range of the mesangial cell. This enhancement can disrupt the controlled, localized intercellular signaling that occurs in health and thus contribute to the exacerbation of diabetic kidney damage. Previously, many models have been developed to study the parameters that impact the signaling range of cells; however, the mathematical interrogation of intercellular signaling in the context of diabetic kidney damage had not been previously done. Additionally, the novel insight gained from this mathematical study also enhances our understanding of how pathological tissue damage induced by diabetes contributes to the disruption of cellular function.

References

1. Jitraknatee, J., C. Ruengorn, and S. Nochaiwong, 2020. Prevalence and Risk Factors of Chronic Kidney Disease among Type 2 Diabetes Patients: A Cross-Sectional Study in Primary Care Practice. Scientific Reports 10:1–10
2. Schlöndorff, D., and B. Banas, 2009. The Mesangial Cell Revisited: No Cell Is an Island. Journal of the American Society of Nephrology 20:1179–1187
3. Lindahl, P., M. Hellström, M. Kalén, L. Karlsson, M. Pekny, M. Pekna, P. Soriano, and C. Betsholtz, 1998. Paracrine PDGF-β/PDGF-Rβ signaling controls mesangial cell development in kidney glomeruli. Development 125:3313–3322

Acknowledgment

This work was supported by the National Science Foundation grant 1845117 and the University at Buffalo.