(285b) Intercellular Biochemical Cross-Talk at the Onset of Diabetic Kidney Disease | AIChE

(285b) Intercellular Biochemical Cross-Talk at the Onset of Diabetic Kidney Disease


Ford Versypt, A. N. - Presenter, Oklahoma State University
Pilvankar, M. R., Oklahoma State University
Ruggiero, S. M., Oklahoma State University
Sartin, A. D., Oklahoma State University
Streeter, C., Oklahoma State University
Diabetic kidney disease (DKD) is among the severe complications of diabetes and is the primary cause for end-stage kidney failure. Hyperglycemia is the condition of excess glucose that can lead to diabetic complications and contribute to the loss of kidney function. Each kidney includes thousands of glomeruli that are comprised of a network of capillaries through which blood is filtered. The glomerular filtration barrier is a highly specialized interface made up of glomerular endothelial cells, basement membrane, and podocytes. Podocytes are terminally differentiated epithelial cells that form the outermost layer of the glomerular filtration barrier and normally prevent leakage of protein, such as albumin into the urine (a condition known as proteinuria or albuminuria). Mesangial cells are another type of specialized kidney cells that form the central stalk of the glomerulus and are known to interact closely with other cells including podocytes. Studies have shown that intercellular biochemical cross-communication between all of these kidney cells is vital in maintaining the structural and functional integrity of the glomeruli. Podocyte depletion and damaging structural changes around the mesangial cells are key predictors of DKD progression. There is evidence suggesting that the tissue damage is caused by signaling pathways and interactions between podocytes and mesangial cells. However, these are several interconnected pathways, and the tissue damage is not immediately detectable with non-invasive clinical methods until after proteinuria develops. Hence, a quantitative approach is used to understand and predict and design therapies to slow the progression of DKD before significant podocyte damage occurs.

While the pathophysiological mechanisms of glomerular injury are still unclear, increasing evidence suggests a key role of pathways involving angiotensin II (ANG II) and transcription growth factor-beta (TGF-β). Podocytes express a local renin-angiotensin system (RAS), which is a hormone system that produces angiotensin II (ANG II). RAS is known to be triggered in hyperglycemic conditions, leading to increase in the production of ANG II. Elevated ANG II levels have been associated with several deleterious effects on podocytes, thus contributing to the progression of DKD. Suppressing the elevated ANG II is one of the most common therapeutic approaches to slow the DKD progression. We have developed an ODE-based PK/PD model of glucose-stimulated RAS dynamics in podocytes using MATLAB. The model predicts the effects of different dosages of pharmaceutical drugs on the concentrations of ANG II in local podocyte RAS. Glucose dependency is added to the model through enzymatic parameters that can help predict ANG II for different glucose levels. The model is parametrized for the pharmaceutical drug-benazepril in the cases of normal and impaired kidney function and can be extended to study the effects of other similar pharmaceutical drugs. The model can also take patient specific glucose dynamics data as a model input to predict ANG II levels and required drug dosage to suppress elevated ANG II levels inside of podocytes.

TGF-β increases in hyperglycemic conditions via a mechanism mediated by ANG II that triggers podocyte injury. TGF-β has been implicated in human glomerular diseases and has been shown to play a key role overexpression of extracellular matrix proteins in the mesangial space and thickening of the glomerular basement membrane, eventually leading to podocyte loss. We extended our podocyte RAS model that predicted the effect of different glucose conditions on ANG II to predict the downstream effects of glucose and ANG II on TGF-β production. The model accounts for the production of TGF-β by glucose and ANG II that is synthesized by glucose-dependent as well as glucose-independent mechanisms.

Even though multiple studies implicated that TGF-β can be stimulated by glucose and ANG II, there is evidence suggesting that these factors do not contribute to increasing production of TGF-β in podocyte cells. On the other hand, stimulation by glucose and ANG II has shown to significantly enhance TGF-β synthesis in mesangial cells. Experimental studies suggest cross-communication of TGF-β between podocytes and mesangial cells, activating multiple signaling pathways that lead to mesangial matrix accumulation, podocyte damage, fibrosis and eventually to kidney failure. However, the exact mechanism of all these processes as they interact between different cells types is not yet clearly understood. Our work focuses on these interactions between and within individual cell types and predicts the effect of changing input conditions like glucose on the downstream effects like TGF- β concentration on podocyte loss and mesangial matrix remodeling.

We also relate glucose conditions to the nephrin loss and resulting urinary protein concentration. Nephrin is a podocyte membrane component that plays a critical role in maintaining the structure and function of the glomerular filtration barrier. Clinical studies have shown that nephrin is reduced in diabetic conditions causing increased protein concentration in urine and is a key mediator of diabetic nephropathy. This model is a quantitative approach towards understanding the threshold where nephrin loss causes long-term damage to the kidney that is clinically predictable from the urine protein concentration.

We are developing a computational approach to understand the cross-communication between different layers or cell-types of the filtration barrier. We are combining the reaction network model with transport equations to study the movement of albumin and glucose through different layers of the filtration barrier. The model structure has two layers. The bottom layer is the mesangium layer, which is made up of mesangial cells and fibers. The top layer is the filtration layer, which is made up of the glomerular basement membrane and podocytes. Glucose can travel through the mesangium layer and enter the filtration layer while albumin can only travel through the mesangium layer. This model shows how high glucose affects the mesangial cells as glucose moves through and stimulates various biochemical networks in layers of filtration barrier and how the structure of the tissue is damaged gradually over time.

The overall objective is to connect these different model components together into a multiscale computational model to get a better understanding of different biochemical and physical processes in glomerular kidney cells that lead to the progression of kidney disease. Quantitative descriptions of the intercellular cross-talks are scarce in the literature. This is the first simulation of the theory of the crosstalk between different kidney cells describing contributions to structural and functional damage in DKD due to biochemical factors. The ability to track transport of glucose between different filtration layers, its effect on ANG II, TGF-β, and nephrin will enable prediction of the downstream effects of hyperglycemia and characterize pathophysiological features of DKD progression.