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.

中文翻译：

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糖尿病小鼠血液动力学机制和肾小球性高血压后果的数学模型。

许多用于糖尿病肾病的临床前期有希望的疗法未能在人类中提供功效，这反映出啮齿动物模型与人类疾病之间定量的翻译理解有限。为了定量弥合物种间的差异，我们采用了人与小鼠之间肾功能的数学模型，并结合了糖尿病和肾切除术的适应性和病理机制来描述实验观察到的db / db和db /肾小球滤过率（GFR）和蛋白尿的变化。 db UNX（单肾切除术）小鼠模型。改变少量参数，该模型再现了肾功能的种间差异。考虑到通过钠葡萄糖共转运蛋白2（SGLT2）对葡萄糖和Na +的重吸收，在正常情况下，将血糖和Na +摄入量增加到db / db水平，在数学上重现了在db / db小鼠中实验观察到的肾小球超滤现象。这是由于近端肾小管对钠的重吸收增加，肾小球毛细血管静水压力（P gc）升高，以通过增加GFR恢复钠平衡。结合升高的P gc的适应性和伤害性作用，我们显示肾小球前小动脉肥大可以使压力更直接地传递到肾小球，而平均动脉压升高较小。肾小球肥大可以使给定的P gc的GFR更高；与P gc驱动的肾小球硬化和肾单位流失会随着时间的推移降低GFR，同时进一步增加P gc并引起中度蛋白尿，与实验数据一致。施加于糖尿病的UNX进一步增加了P gc，引起更快的GFR下降和广泛的蛋白尿，也与实验数据一致。该模型为超滤和蛋白尿的进展提供了机械解释，这将有助于将新型疗法的功效从小鼠模型转化为人类。