鸟苷林和尿鸟苷林可在缺乏鸟苷酸环化酶-C受体的小鼠中诱导利钠作用。

Guanylin and uroguanylin induce natriuresis in mice lacking guanylyl cyclase-C receptor.

作者信息

Carrithers Stephen L, Ott Cobern E, Hill Michael J, Johnson Brett R, Cai Weiyan, Chang Jason J, Shah Rajesh G, Sun Congmei, Mann Elizabeth A, Fonteles Manasses C, Forte Leonard R, Jackson Brian A, Giannella Ralph A, Greenberg Richard N

机构信息

Department of Internal Medicine, Division of Infectious Diseases, Lexington VA Medical Center and University of Kentucky, Lexington, Kentucky 40506, USA.

出版信息

Kidney Int. 2004 Jan;65(1):40-53. doi: 10.1111/j.1523-1755.2004.00375.x.

DOI:10.1111/j.1523-1755.2004.00375.x

PMID:14675035

Abstract

BACKGROUND

Guanylin (GN) and uroguanylin (UGN) are intestinally derived peptide hormones that are similar in structure and activity to the diarrhea-causing Escherichia coli heat-stable enterotoxins (STa). These secretagogues have been shown to affect fluid, Na+, K+, and Cl- transport in both the intestine and kidney, presumably by intracellular cyclic guanosine monophosphate (cGMP)-dependent signal transduction. However, the in vivo consequences of GN, UGN, and STa on renal function and their mechanism of action have yet to be rigorously tested.

METHODS

We hypothesized that intravenous administration of GN, UGN, or STa would cause an increase in natriuresis in wild-type mice via cGMP and guanylyl cyclase-C (GC-C, Gucy2c), the only known receptor for these peptide-hormones, and that the peptide-induced natriuresis would be blunted in genetically altered mice devoid of GC-C receptors (GC-C(-/-) null).

RESULTS

In wild-type mice using a modified renal clearance model, GN, UGN, and STa elicited significant natriuresis, kaliuresis, and diuresis as well as increased urinary cGMP levels in a time- and dose-dependent fashion. Absolute and fractional urinary sodium excretion levels were greatest approximately 40 minutes following a bolus infusion with pharmacologic doses of these peptides. Unexpectedly, GC-C(-/-) null mice also responded to the GN peptides similarly to that observed in wild-type mice. Glomerular filtration rate (GFR), blood pressure, and plasma cGMP in the mice (wild-type or GC-C(-/-) null) did not significantly vary between the vehicle- and peptide-treatment groups. The effects of UGN may also influence long-term renal function due to down-regulation of the Na+/K+ ATPase gamma-subunit and the Cl- channel ClC-K2 by 60% and 75%, respectively, as assessed by differential display polymerase chain reaction (PCR) (DD-PCR) and Northern blot analysis of kidney mRNA from mice treated with UGN.

CONCLUSION

GN, UGN, and STa act on the mouse kidney, in part, through a cGMP-dependent, GC-C-independent mechanism, causing significant natriuresis by renal tubular processes. UGN may have further long-term effects on the kidney by altering the expression of such transport-associated proteins as Na+/K+ ATPase and ClC-K2.

摘要

背景

鸟苷林（GN）和尿鸟苷林（UGN）是源自肠道的肽类激素，其结构和活性与致腹泻的大肠杆菌热稳定肠毒素（STa）相似。这些促分泌素已被证明会影响肠道和肾脏中的液体、Na⁺、K⁺和Cl⁻转运，推测是通过细胞内环磷酸鸟苷（cGMP）依赖性信号转导实现的。然而，GN、UGN和STa对肾功能的体内影响及其作用机制尚未得到严格测试。

方法

我们假设静脉注射GN、UGN或STa会通过cGMP和鸟苷酸环化酶-C（GC-C，Gucy2c）使野生型小鼠的尿钠排泄增加，GC-C是这些肽类激素唯一已知的受体，并且在缺乏GC-C受体的基因改造小鼠（GC-C（-/-）敲除小鼠）中，肽诱导的尿钠排泄会减弱。

结果

在使用改良肾清除模型的野生型小鼠中，GN、UGN和STa以时间和剂量依赖性方式引起显著的尿钠排泄、尿钾排泄和利尿，同时尿cGMP水平升高。在给予这些肽的药理剂量进行推注后约40分钟，绝对和分数尿钠排泄水平最高。出乎意料的是，GC-C（-/-）敲除小鼠对GN肽的反应与野生型小鼠相似。在载体处理组和肽处理组之间，小鼠（野生型或GC-C（-/-）敲除小鼠）的肾小球滤过率（GFR）、血压和血浆cGMP没有显著差异。通过差异显示聚合酶链反应（PCR）（DD-PCR）和对用UGN处理的小鼠肾脏mRNA进行Northern印迹分析评估，UGN的作用还可能分别使Na⁺/K⁺ ATP酶γ亚基和Cl⁻通道ClC-K2下调60%和75%，从而影响长期肾功能。