We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Mathematical model of hemodynamic mechanisms and consequences of glomerular hypertension in diabetic mice.
- Authors
Mahato, Hari Shankar; Ahlstrom, Christine; Jansson-Löfmark, Rasmus; Johansson, Ulrika; Helmlinger, Gabriel; Hallow, K. Melissa
- Abstract
Many preclinically promising therapies for diabetic kidney disease fail to provide efficacy in humans, reflecting limited quantitative translational understanding between rodent models and human disease. To quantitatively bridge interspecies differences, we adapted a mathematical model of renal function from human to mice, and incorporated adaptive and pathological mechanisms of diabetes and nephrectomy to describe experimentally observed changes in glomerular filtration rate (GFR) and proteinuria in db/db and db/db UNX (uninephrectomy) mouse models. Changing a small number of parameters, the model reproduced interspecies differences in renal function. Accounting for glucose and Na+ reabsorption through sodium glucose cotransporter 2 (SGLT2), increasing blood glucose and Na+ intake from normal to db/db levels mathematically reproduced glomerular hyperfiltration observed experimentally in db/db mice. This resulted from increased proximal tubule sodium reabsorption, which elevated glomerular capillary hydrostatic pressure (Pgc) in order to restore sodium balance through increased GFR. Incorporating adaptive and injurious effects of elevated Pgc, we showed that preglomerular arteriole hypertrophy allowed more direct transmission of pressure to the glomerulus with a smaller mean arterial pressure rise; Glomerular hypertrophy allowed a higher GFR for a given Pgc; and Pgc-driven glomerulosclerosis and nephron loss reduced GFR over time, while further increasing Pgc and causing moderate proteinuria, in agreement with experimental data. UNX imposed on diabetes increased Pgc further, causing faster GFR decline and extensive proteinuria, also in agreement with experimental data. The model provides a mechanistic explanation for hyperfiltration and proteinuria progression that will facilitate translation of efficacy for novel therapies from mouse models to human. Mathematical model of mouse diabetic kidney injury: Many drugs for diabetic kidney disease appear to work in rodents, but fail in humans, reflecting incomplete understanding of disease processes. A team led by Melissa Hallow at the University of Georgia has developed a mathematical model that explains how elevated blood glucose in diabetes causes kidney injury in mice. They first showed that normal human, rat, or mouse kidney physiology could be reproduced with the same model by changing a small number of parameters. They then showed that diabetes-induced increases in sodium reabsorption cause unintuitive changes in kidney function that increase pressure on glomerular capillaries, causing protein leakage and nephron loss. The model reproduced faster disease progression observed in diabetic mice who have had one kidney removed. This mathematical understanding of diabetic kidney injury may improve translation of novel therapies from mice to human.
- Subjects
HEMODYNAMICS; HYPERTENSION; DIABETIC nephropathies; GLOMERULAR filtration rate; LABORATORY mice; MATHEMATICAL models
- Publication
NPJ Systems Biology & Applications, 2018, Vol 4, Issue 1, pN.PAG
- ISSN
2056-7189
- Publication type
Article
- DOI
10.1038/s41540-018-0077-9