Abstract: SA-PO102
Mechanistic Modelling of the Linkage Between Proximal Tubule Cell Sublethal Injury and Tubular Sodium Reabsorption Impairment
Session Information
- AKI: Mechanisms - Primary Injury and Repair - II
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Hamzavi, Nader, DILIsym Services Inc., a Simulation Plus Company, Research Triangle Park, North Carolina, United States
- Gebremichael, Yeshitila, DILIsym Services Inc., a Simulation Plus Company, Research Triangle Park, North Carolina, United States
- Woodhead, Jeffrey L., DILIsym Services Inc., a Simulation Plus Company, Research Triangle Park, North Carolina, United States
- Tallapaka, Shailendra, DILIsym Services Inc., a Simulation Plus Company, Research Triangle Park, North Carolina, United States
- Siler, Scott Q., DILIsym Services Inc., a Simulation Plus Company, Research Triangle Park, North Carolina, United States
- Howell, Brett A., DILIsym Services Inc., a Simulation Plus Company, Research Triangle Park, North Carolina, United States
Background
Renal epithelial cell injury, a prominent feature of drug-induced acute kidney injury (AKI), is characterized by loss of brush border and cellular polarity of proximal tubular cells (PTCs). The key alterations caused by sublethal injury involve impaired energetics and associated disruptions in cytoskeletal structure and sodium transporters activity. A mechanistic model relating AKI mediated cellular injury with renal tubular dysfunction is needed to address the complexity of renal physiology.
Methods
We developed a model of sublethal PTCs injury and sodium reabsorption impairment within the framework of RENAsym, a quantitative systems toxicology (QST) model of drug-induced AKI under development. The mathematical model represents major components of renal sublethal injury in a system of equations accounting for ATP decline, microfilament redistribution, and Na+/K+ ATPase activity reduction. The model equations were parametrized with an experimental study in which induced sublethal injury in rats, by selectively inhibiting cortical ATP production using maleic acid, was investigated and the effect of dose-dependent ATP decrement on apical F-actin networks and tubular sodium reabsorption was measured [1].
Results
Microfilament disruption was quantified with ATP decrement and then related to translocation-based loss of Na+/K+-ATPase, while a decline in the molecular activity of a sodium pump was directly related to ATP decrement. The model recapitulated the link between ATP decrement and sodium reabsorption impairment through the intermediate pathological pathways of microfilament redistribution and Na+/K+ ATPase activity reduction. Simulations of varying ATP decrement reveals a sharp decline in sodium reabsorption as the relative ATP decrement exceeds 40%, in accord with observations [1].
Conclusion
A mechanistic model of subcellular injury is developed to link cellular ATP decrement and tubular sodium reabsorption impairment. The model serves as a bridge between cellular toxicity and renal tubular functional impairment, allowing mechanistic prediction of AKI induced renal hemodynamics.
Funding
- NIDDK Support