胰岛素调节的氨肽酶是对急性低渗应激反应时排泄水分所必需的。

IF 3.7 2区 医学 Q1 PHYSIOLOGY American Journal of Physiology-renal Physiology Pub Date : 2023-06-01 Epub Date: 2023-03-30 DOI:10.1152/ajprenal.00318.2022
Yvonne Zuchowski, Joshua Carty, Andrew S Terker, Fabian Bock, Jonathan B Trapani, Gautam Bhave, Jason A Watts, Susanna Keller, Mingzhi Zhang, Roy Zent, Raymond C Harris, Juan Pablo Arroyo
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引用次数: 0

摘要

本研究的目的是了解缺乏胰岛素调节的氨基肽酶(IRAP)的小鼠对急性水负荷的反应。为了使哺乳动物对急性水负荷有适当的反应,血管加压素活性需要降低。IRAP在体内降解血管加压素。因此,我们假设缺乏IRAP的小鼠降解加压素的能力受损,因此具有持续的尿浓度。年龄匹配的8-12周龄IRAP野生型(WT)和敲除(KO)雄性小鼠用于所有实验。在水负荷前和水负荷后1小时测量血液电解质和尿液渗透压(通过腹膜内注射~2 mL无菌水)。从IRAP WT和KO小鼠收集尿液,用于在基线和施用血管加压素2型受体拮抗剂OPC-31260(10mg/kg ip)1小时后的尿液渗透压测量。在基线和急性水负荷1小时后对肾脏进行免疫荧光和免疫印迹分析。IRAP表达于肾小球、Henle粗升环、远端小管、连接管和集合管。与WT小鼠相比,IRAP KO小鼠的尿液渗透压升高,这是由于水通道蛋白2(AQP2)的膜表达较高,在施用OPC-31260后,AQP2恢复到对照组。IRAP KO小鼠在急性水负荷后出现低钠血症,因为它们由于AQP2的表面表达增加而无法增加自由水排泄。总之,由于持续的加压素刺激AQP2.NEW和NOTEWORTHY胰岛素调节的氨基肽酶(IRAP)可降解加压素,但其在尿液浓度和稀释中的作用尚不清楚。在这里,我们发现IRAP缺陷小鼠在基线时具有高的尿渗透压,并且不能对水负荷做出反应而排出游离水。这些结果揭示了IRAP在尿液浓度和稀释中的新的调节作用。
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Insulin-regulated aminopeptidase is required for water excretion in response to acute hypotonic stress.

The objective of this study was to understand the response of mice lacking insulin-regulated aminopeptidase (IRAP) to an acute water load. For mammals to respond appropriately to acute water loading, vasopressin activity needs to decrease. IRAP degrades vasopressin in vivo. Therefore, we hypothesized that mice lacking IRAP have an impaired ability to degrade vasopressin and, thus, have persistent urinary concentration. Age-matched 8- to 12-wk-old IRAP wild-type (WT) and knockout (KO) male mice were used for all experiments. Blood electrolytes and urine osmolality were measured before and 1 h after water load (∼2 mL sterile water via intraperitoneal injection). Urine was collected from IRAP WT and KO mice for urine osmolality measurements at baseline and after 1 h administration of the vasopressin type 2 receptor antagonist OPC-31260 (10 mg/kg ip). Immunofluorescence and immunoblot analysis were performed on kidneys at baseline and after 1 h acute water load. IRAP was expressed in the glomerulus, thick ascending loop of Henle, distal tubule, connecting duct, and collecting duct. IRAP KO mice had elevated urine osmolality compared with WT mice due to higher membrane expression of aquaporin 2 (AQP2), which was restored to that of controls after administration of OPC-31260. IRAP KO mice developed hyponatremia after an acute water load because they were unable to increase free water excretion due to increased surface expression of AQP2. In conclusion, IRAP is required to increase water excretion in response to an acute water load due to persistent vasopressin stimulation of AQP2.NEW & NOTEWORTHY Insulin-regulated aminopeptidase (IRAP) degrades vasopressin, but its role in urinary concentration and dilution is unknown. Here, we show that IRAP-deficient mice have a high urinary osmolality at baseline and are unable to excrete free water in response to water loading. These results reveal a novel regulatory role for IRAP in urine concentration and dilution.

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来源期刊
CiteScore
8.40
自引率
7.10%
发文量
154
审稿时长
2-4 weeks
期刊介绍: The American Journal of Physiology - Renal Physiology publishes original manuscripts on timely topics in both basic science and clinical research. Published articles address a broad range of subjects relating to the kidney and urinary tract, and may involve human or animal models, individual cell types, and isolated membrane systems. Also covered are the pathophysiological basis of renal disease processes, regulation of body fluids, and clinical research that provides mechanistic insights. Studies of renal function may be conducted using a wide range of approaches, such as biochemistry, immunology, genetics, mathematical modeling, molecular biology, as well as physiological and clinical methodologies.
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