Molecular changes in proximal tubule function in diabetes mellitus
Molecular changes in proximal tubule function in diabetes mellitus
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DOI：
10.1111/j.1440-1681.2004.04001.x
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发表时间：
2004-05-01
影响因子：
2.9
通讯作者：
Poronnik, P
中科院分区：
文献类型：
--
作者：
Hryciw, DH;Lee, EM;Poronnik, P
1.糖尿病肾病最初与高血压和尿白蛋白排泄增加有关。高血压是由肾脏增加的盐和水潴留导致的体积扩张增强介导的。尿白蛋白增加不仅是由于肾小球渗漏增加，而且是由于近曲小管白蛋白重吸收减少所致。这两种现象背后的精确分子机制以及Na+潴留增加与蛋白尿之间是否存在任何联系仍不清楚。2．有重要证据表明，近曲小管 Na+/H+ 交换异构体 3 (NHE3) 增加的 Na+ 潴留可能在某些形式的高血压中发挥作用。糖尿病模型中 NHE3 活性的增加可能部分解释了在糖尿病肾病患者中观察到的盐潴留增强的原因。3． NHE3 还在近曲小管中受体介导的白蛋白摄取中发挥作用。白蛋白的摄取需要组装大分子复合物，该复合物被认为包括巨蛋白/cubulin受体、NHE3、液泡型H+-ATP酶(v-H+-ATP酶)、Cl-通道CIC-5以及与肌动蛋白细胞骨架的相互作用。 NHE3似乎存在于两个功能不同的膜域中，一个涉及Na+重吸收，另一个涉及白蛋白摄取。4．本综述重点关注来自体内研究以及细胞培养模型中的补充研究的证据，证明 NHE3 在 Na+ 保留和白蛋白摄取方面具有双重作用。我们提出了一种可能的机制，通过这种机制，糖尿病中近曲小管白蛋白摄取机制的破坏可能导致 Na+ 潴留和蛋白尿增加。
1. Diabetic kidney disease is initially associated with hypertension and increased urinary albumin excretion. The hypertension is mediated by enhanced volume expansion due to enhanced salt and water retention by the kidney. The increased urinary albumin is not only due to increased glomerular leak, but also to a decrease in albumin reabsorption by the proximal tubule. The precise molecular mechanisms underlying these two phenomena and whether there is any link between the increase in Na+ retention and proteinuria remain unresolved.2. There is significant evidence to suggest that increased Na+ retention by the proximal tubule Na+/H+ exchanger isoform 3 (NHE3) can play a role in some forms of hypertension. Increased NHE3 activity in models of diabetes mellitus may explain, in part, the enhanced salt retention observed in patients with diabetic kidney disease.3. The NHE3 also plays a role in receptor-mediated albumin uptake in the proximal tubule. The uptake of albumin requires the assembly of a macromolecular complex that is thought to include the megalin/cubulin receptor, NHE3, the vacuolar type H+-ATPase (v-H+-ATPase), the Cl- channel CIC-5 and interactions with the actin cytoskeleton. The NHE3 seems to exist in two functionally distinct membrane domains, one involved with Na+ reabsorption and the other involved in albumin uptake.4. The present review focuses on the evidence derived from in vivo studies, as well as complementary studies in cell culture models, for a dual role of NHE3 in both Na+ retention and albumin uptake. We suggest a possible mechanism by which disruption of the proximal tubule albumin uptake mechanism in diabetes mellitus may lead to both increased Na+ retention and proteinuria.