(329b) Modeling Cellular Signaling and Mesangial Fibrosis during Diabetic Kidney Disease

In the U.S. alone over 250,000 people use dialysis or have received a kidney transplant due to diabetic kidney failure. Although we have come a long way in the treatment of diabetes, kidney failure due to diabetic kidney damage is still prevalent, and the need for increasing our understanding of kidney damage to enable the development of better treatment methods is ever present. The goal of this research is to develop computational models to better understand the kidney damage that occurs due to diabetic kidney disease.

In the kidney glomerulus, the filtration unit of the kidney, lies a network of capillaries that are surrounded by interstitial tissue called the mesangium. In health, the mesangium acts as a support for the capillaries; however, during diabetic kidney disease, the mesangium expands due to excess accumulation of collagen (fibrosis) and causes damage to the cellular environment around it. This mesangial expansion is not only a hallmark of kidneys damaged by diabetes but also many other chronic kidney diseases that lead to kidney failure. There has been a lot of research effort in trying to figure out the cause of the mesangial expansion. Researchers have found high glucose-induced dysfunction in the mesangial cell, a cell native to the mesangium, to be one of the main reasons for mesangial expansion. The mesangial cell dysfunction is mediated by the overstimulation of key signaling and cellular communication molecules such as TGF-beta and Ang II, which play a key role in perturbing the function of downstream collagen metabolism molecules such as MMP and TIMP, leading to the accumulation of excess collagen. The complexity of the interactions necessitates the development of computational models to understand the whole, yet there are few computational models of mesangial expansion and even fewer that study the effect of the mesangial expansion on cellular communication and signaling in the glomerulus.

In this work, we present a multiscale, computational model of mesangial fibrosis to study its effect on cellular signaling and communication. Our computational model considers the impact of mesangial cell mediated mesangial expansion on cellular signaling and communication through multiscale modeling of extracellular matrix remodeling and macromolecular transport. We are incorporating a cellular environment using a cellular Potts type of agent-based stochastic model, modeling mesangial expansion using fundamental biological principles of collagen fiber growth and accumulation, solving macromolecular transport equations defined by continuous reaction-diffusion partial differential equations, and linking them all using Python and CompuCell3D, a multiscale tissue simulation software. Novel and biologically sound, the model captures mesangial fibrosis and provides insight into cellular communication during diabetic kidney damage.