PDF(Pubmed)
Abstract：
In early diabetic nephropathy (DN), recent studies have shown that albuminuria stems mostly from alterations in tubular function rather than from glomerular damage. Several factors in DN, including hyperfiltration, hypertrophy and reduced abundance of the albumin receptors megalin and cubilin, affect albumin endocytosis in the proximal tubule (PT). To assess their respective contribution, we developed a model of albumin handling in the rat PT that couples the transport of albumin to that of water and solutes. Our simulations suggest that, under basal conditions, ∼75% of albumin is retrieved in the S1 segment. The model predicts negligible uptake in S3, as observed experimentally. It also accurately predicts the impact of acute hyperglycaemia on urinary albumin excretion. Simulations reproduce observed increases in albumin excretion in early DN by considering the combined effects of increased glomerular filtration rate (GFR), osmotic diuresis, hypertrophy, and megalin and cubilin downregulation, without stipulating changes in glomerular permselectivity. The results indicate that in isolation, glucose-elicited osmotic diuresis and glucose transporter upregulation raise albumin excretion only slightly. Enlargement of PT diameter not only augments uptake via surface area expansion, but also reduces fluid velocity and thus shear stress-induced stimulation of endocytosis. Overall, our model predicts that downregulation of megalin and cubilin and hyperfiltration both contribute significantly to increasing albumin excretion in rats with early-stage diabetes. The results also suggest that acute sodium-glucose cotransporter 2 inhibition lowers albumin excretion only if GFR decreases sufficiently, and that angiotensin II receptor blockers mitigate urinary albumin loss in early DN in large part by upregulating albumin receptor abundance. KEY POINTS: The urinary excretion of albumin is increased in early diabetic nephropathy (DN). It is difficult to experimentally disentangle the multiple factors that affect the renal handling of albumin in DN. We developed a mathematical model of albumin transport in the rat proximal tubule (PT) to examine the impact of elevated plasma glucose, hyperfiltration, PT hypertrophy and reduced abundance of albumin receptors on albumin uptake and excretion in DN. Our model predicts that glucose-elicited osmotic diuresis per se raises albumin excretion only slightly. Conversely, increases in PT diameter and length favour reduced albumin excretion. Our results suggest that downregulation of the receptors megalin and cubilin in PT cells and hyperfiltration both contribute significantly to increasing albumin excretion in DN. The model helps to better understand the mechanisms underlying urinary loss of albumin in early-stage diabetes, and the impact of specific treatments thereupon.
摘要：
在早期糖尿病肾病（DN）中，最近的研究表明，蛋白尿主要源于肾小管功能的改变，而不是肾小球损伤。DN中的几个因素，包括超滤,肥大和白蛋白受体megalin和cubilin的丰度降低，影响近端小管（PT）的白蛋白内吞作用。评估他们各自的贡献，我们开发了一种大鼠PT中白蛋白处理模型，该模型将白蛋白的转运与水和溶质的转运相结合。我们的模拟表明，在基础条件下，75%的白蛋白在S1段中被回收。如实验观察到的，该模型预测S3中的摄取可忽略不计。它还可以准确预测急性高血糖对尿白蛋白排泄的影响。通过考虑肾小球滤过率（GFR）增加的综合作用，模拟再现了早期DN中观察到的白蛋白排泄增加。渗透性利尿,肥大,以及megalin和cubilin下调，没有规定肾小球选择性的变化。结果表明，孤立地，葡萄糖引起的渗透性利尿和葡萄糖转运蛋白上调仅略微增加白蛋白排泄。PT直径的扩大不仅通过表面积扩大来增加吸收，但也会降低流体速度，从而降低剪切应力诱导的内吞刺激。总的来说,我们的模型预测,在早期糖尿病大鼠中,megalin和cubilin的下调和超滤均显著有助于增加白蛋白的排泄.结果还表明，只有当GFR充分降低时，急性钠-葡萄糖协同转运蛋白2抑制才会降低白蛋白排泄。血管紧张素II受体阻滞剂通过上调白蛋白受体丰度在很大程度上减轻了早期DN的尿白蛋白丢失。关键词：早期糖尿病肾病（DN）尿白蛋白排泄增加。很难在实验上解开影响DN中白蛋白肾脏处理的多种因素。我们开发了大鼠近端小管（PT）中白蛋白转运的数学模型，以检查血浆葡萄糖升高的影响，超滤,PT肥大和白蛋白受体丰度降低对DN中白蛋白摄取和排泄的影响。我们的模型预测，葡萄糖引起的渗透性利尿本身仅略微增加白蛋白排泄。相反，PT直径和长度的增加有利于白蛋白排泄的减少。我们的结果表明，PT细胞中受体megalin和cubilin的下调和超滤均显着增加DN中的白蛋白排泄。该模型有助于更好地了解早期糖尿病患者尿白蛋白丢失的潜在机制。以及特定治疗方法的影响。
