新型可溶性鸟苷酸环化酶激活剂增加肾小球 cGMP，诱导血管舒张，改善小鼠肾脏血流。
Novel soluble guanylyl cyclase activators increase glomerular cGMP, induce vasodilation and improve blood flow in the murine kidney.
机构信息
Interfakultäres Institut für Biochemie (IFIB), University of Tübingen, Tübingen, Germany.
Institute of Vegetative Physiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
出版信息
Br J Pharmacol. 2022 Jun;179(11):2476-2489. doi: 10.1111/bph.15586. Epub 2021 Jul 3.
BACKGROUND AND PURPOSE
Generation of cGMP via NO-sensitive soluble guanylyl cyclase (sGC) has been implicated in the regulation of renal functions. Chronic kidney disease (CKD) is associated with decreased NO bioavailability, increased oxidative stress and oxidation of sGC to its haem-free form, apo-sGC. Apo-sGC cannot be activated by NO, resulting in impaired cGMP signalling that is associated with chronic kidney disease progression. We hypothesised that sGC activators, which activate apo-sGC independently of NO, increase renal cGMP production under conditions of oxidative stress, thereby improving renal blood flow (RBF) and kidney function.
EXPERIMENTAL APPROACH
Two novel sGC activators, runcaciguat and BAY-543, were tested on murine kidney. We measured cGMP levels in real time in kidney slices of cGMP sensor mice, vasodilation of pre-constricted glomerular arterioles and RBF in isolated perfused kidneys. Experiments were performed at baseline conditions, under L-NAME-induced NO deficiency, and in the presence of oxidative stress induced by ODQ.
KEY RESULTS
Mouse glomeruli showed NO-induced cGMP increases. Under baseline conditions, sGC activator did not alter glomerular cGMP concentration or NO-induced cGMP generation. In the presence of ODQ, NO-induced glomerular cGMP signals were markedly reduced, whereas sGC activator induced strong cGMP increases. L-NAME and ODQ pretreated isolated glomerular arterioles were strongly dilated by sGC activator. sGC activator also increased cGMP and RBF in ODQ-perfused kidneys.
CONCLUSION AND IMPLICATION
sGC activators increase glomerular cGMP, dilate glomerular arterioles and improve RBF under disease-relevant oxidative stress conditions. Therefore, sGC activators represent a promising class of drugs for chronic kidney disease treatment.
LINKED ARTICLES
This article is part of a themed issue on cGMP Signalling in Cell Growth and Survival. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc.
背景和目的
通过一氧化氮（NO）敏感型可溶性鸟苷酸环化酶（sGC）生成 cGMP 已被牵涉到对肾脏功能的调节中。慢性肾病（CKD）与 NO 生物利用度降低、氧化应激增加以及 sGC 氧化为不含血红素的形式即脱辅基 sGC（apo-sGC）有关。apo-sGC 不能被 NO 激活，导致 cGMP 信号转导受损，这与慢性肾病的进展有关。我们假设 sGC 激活剂可独立于 NO 激活 apo-sGC，在氧化应激条件下增加肾脏 cGMP 的产生，从而改善肾血流（RBF）和肾功能。
实验方法
在 cGMP 传感器小鼠的肾切片中实时测量 cGMP 水平，在分离的灌注肾脏中测量预先收缩的肾小球小动脉的血管舒张和 RBF。在基础条件下、在 L-NAME 诱导的 NO 缺乏下以及在 ODQ 诱导的氧化应激下进行实验。
主要结果
小鼠肾小球显示出由 NO 诱导的 cGMP 增加。在基础条件下，sGC 激活剂不会改变肾小球 cGMP 浓度或 NO 诱导的 cGMP 生成。在 ODQ 存在下，NO 诱导的肾小球 cGMP 信号明显减少，而 sGC 激活剂诱导了强烈的 cGMP 增加。预先用 L-NAME 和 ODQ 处理的分离肾小球小动脉被 sGC 激活剂强烈扩张。sGC 激活剂还增加了 ODQ 灌注肾脏中的 cGMP 和 RBF。
结论和意义
sGC 激活剂在与疾病相关的氧化应激条件下增加肾小球 cGMP、扩张肾小球小动脉并改善 RBF。因此，sGC 激活剂代表了治疗慢性肾病的一类有前途的药物。
相关文章
本文是关于 cGMP 信号转导在细胞生长和存活的主题问题的一部分。要查看本部分中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc。
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