Insights from direct renal insulin infusion: a new hammer for an age-old nail.
Insights from direct renal insulin infusion: a new hammer for an age-old nail.
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直接肾胰岛素输注的见解：旧钉子的新锤子。
DOI：
10.1152/ajprenal.00532.2017
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Bhalla,Vivek
中科院分区：
文献类型：
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作者：
Nizar,JonathanM;Bhalla,Vivek
在生物学中，特别是在肾生理学中，在临床相关现象的观察和潜在机制的阐明之间通常存在延迟，因为研究人员可用的工具（“锤子”）不足，需要开发新的和创新的技术来克服这些障碍。胰岛素在不同组织中的作用就是这样一种现象。自从De Fronzo et al. (1)许多研究者试图弄清楚胰岛素是如何以及是否由于增强的肾钠重吸收而升高血压的，以及这是由于对肾脏、神经系统或脉管系统的直接或间接作用。在最近一期杂志上的一篇文章中，Irsik et al. (4a)报告了一种将胰岛素输送至完整大鼠肾脏的技术，以测量其对肾脏离子处理和血压的直接影响。自从盖顿认识到钠排泄是血容量的关键调节器以来，肾脏在血压测定中的中心作用已得到认可（2）。在过去的几十年中，许多人类研究已经证明高血压与胰岛素抵抗和伴随的高胰岛素血症相关疾病（例如代谢综合征和2型糖尿病）之间存在强相关性。几条证据支持胰岛素在肾脏中起作用以增加血压的假设（9）。胰岛素输注，剂量模拟胰岛素抵抗的高胰岛素血症，减少人体（1）和许多临床前模型中的钠排泄，血清胰岛素浓度与人体血压升高相关（7）。然而，确定可能影响胰岛素的抗利尿和可能的高血压作用的器官和细胞类型的努力一直具有挑战性。为了在大鼠中解决这个问题，Irsik et al. (4a)在对侧肾切除术后，通过放置在一侧肾动脉中的微导管将胰岛素输送到肾脏。作者令人信服地证明，胰岛素输注的全身效应可以忽略不计，因此提供了一个增强的、肾脏限制的胰岛素信号传导而不改变血糖的优雅模型。这些大鼠在1周的慢性输注中出现血压升高;令人惊讶的是，在净钠排泄量没有预先降低。这项工作由Irsik等人。(4a)为下一个关键问题奠定了基础：胰岛素在肾血管系统中的作用足以增加血压吗？到目前为止，胰岛素信号在升高血压中的作用主要集中在胰岛素增加肾单位钠重吸收的能力上，但结果并不一致。虽然几种钠转运蛋白和通道在心肌细胞中上调，
In biology, and particularly in renal physiology, there is often a delay between observations of clinically relevant phenomena and elucidation of the underlying mechanisms, because the tools (“hammers”) available to researchers are insufficient and require development of new and innovative techniques to overcome these hurdles. The role of insulin action in different tissues is one such phenomenon. Since the work of De Fronzo et al.(1), many investigators have tried to tease apart how and if insulin increases blood pressure due to enhanced renal sodium reabsorption and whether this is due to direct or indirect actions on the kidneys, nervous system, or vasculature. In an article in a recent issue of the journal, Irsik et al.(4a) report on a technique to deliver insulin to the intact rat kidney to measure its direct effect on renal ion handling and blood pressure.The central role of the kidney in determination of blood pressure has been appreciated since Guyton’s recognition of sodium excretion as a critical regulator of blood volume (2). Over the past several decades, many studies in humans have demonstrated strong associations between hypertension and conditions associated with insulin resistance and concomitant hyperinsulinemia (eg, metabolic syndrome and type 2 diabetes mellitus). Several lines of evidence support the hypothesis that insulin acts in the kidney to increase blood pressure (9). Insulin infusion, dosed to mimic the hyperinsulinemia of insulin resistance, decreases sodium excretion in humans (1) and in many preclinical models, and serum insulin concentration associates with higher blood pressure in humans (7). However, efforts to determine the organ and cell types that may transduce insulin’s antinatriuretic and possible hypertensive effects have been challenging. To address this issue in rats, Irsik et al.(4a) deliver insulin to the kidney via a microcatheter placed into the renal artery of one kidney after contralateral nephrectomy. The authors demonstrate convincingly that there are negligible systemic effects of the insulin infusion and thus provide an elegant model of enhanced, kidney-restricted insulin signaling without changes in blood glucose. These rats developed increasing blood pressure over 1 wk of chronic infusion; surprisingly, without an antecedent decrease in net sodium excretion. This work by Irsik et al.(4a) lays the groundwork for a critical next question: is insulin action in the renal vasculature sufficient to augment blood pressure? Thus far, the role of insulin signaling to augment blood pressure has mainly focused on insulin’s ability to augment sodium reabsorption in the nephron, but the results have been incongruent. Although several sodium transporters and channels are upregulated in