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Mathematical model of hemodynamic mechanisms and consequences of glomerular hypertension in diabetic mice.

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 (P gc) in order to restore sodium balance through increased GFR. Incorporating adaptive and injurious effects of elevated P gc, 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 P gc; and P gc-driven glomerulosclerosis and nephron loss reduced GFR over time, while further increasing P gc and causing moderate proteinuria, in agreement with experimental data. UNX imposed on diabetes increased P gc 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.

PROVIDER: S-EPMC6288095 | BioStudies |

REPOSITORIES: biostudies

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