Glucose-dependence of Renin-angiotensin system in podocytes cells during diabetic kidney disease

2017 SIAM Conference on Computational Science and Engineering

Abstract. Diabetic kidney disease (DKD) is the primary cause of end-stage renal failure. Damage to podocyte cells is a key indicator in DKD progression. Podocytes are terminally differentiated glomerular epithelial cells that maintain the structure and function of the glomerular filtration barrier in kidneys. Podocytes express an intracellular renin-angiotensin system (RAS) that is different from the systemic RAS and that is altered in hyperglycemia. Studies have shown that the RAS peptide angiotensin II (ANG II) is modulated in hyperglycemic conditions triggering podocyte injury. The progression of DKD could be slowed by controlling the ANG II levels to prevent irreversible podocyte damage and loss. However, experimental evidence for the functional form for glucose-dose- dependency of ANG II is scarce in the literature. Hence, for better understanding of the underlying mechanism, we use mathematical modeling to describe the glucose-stimulated RAS signaling in podocytes that produces ANG II.

We have formulated a mathematical model that describes the glucose-sensitive reaction network that triggers the synthesis of ANG II. The local podocyte RAS signaling pathway is represented by a system of ordinary differential equations to track RAS peptides, enzymes, and receptors without explicit glucose-dependence. Glucose-dependence was added to the model through making the parameters functions of glucose. Literature experimental studies were used to estimate the unknown parameters and kinetic constants for the model under different glucose levels. The results showed a rise in ANG II levels with increasing glucose concentrations consistent with experimental observations. We were able to discriminate between possible models for the glucose dose-dependency of intracellular ANG II production in podocytes. The resulting model can be used to study the effect of different combinations of various ANG II modulating therapies such as ACE inhibitors, which could be useful for drug development.