Functional metabotropic glutamate receptors 1 and 5 are expressed in murine podocytes
Functional metabotropic glutamate receptors 1 and 5 are expressed in murine podocytes
复制标题
功能性代谢型谷氨酸受体 1 和 5 在小鼠足细胞中表达
DOI：
10.1038/ki.2011.406
复制
发表时间：
2012-03-01
影响因子：
19.6
通讯作者：
Qian, Jiaqi
中科院分区：
文献类型：
--
作者：
Gu, Leyi;Liang, Xinyue;Qian, Jiaqi
在非神经细胞中，谷氨酸是一种细胞外信号媒介。由于足细胞有含谷氨酸的囊泡，我们试图确定肾小球细胞中谷氨酸受体的存在和作用。代谢性谷氨酸受体(MGluR)1、5、6和8在小鼠脑和肾小球表达，主要分布在足细胞。在两种蛋白尿模型(嘌呤霉素氨基核苷诱导的Balb/C小鼠和阿霉素诱导的足细胞损伤)中，我们发现选择性mGluR1/5激动剂(S)-3，5-二羟基苯甘氨酸(DHPG)可减轻蛋白尿并促进足细胞标志物WT-1的表达。TUNEL染色显示肾小球WT-1阳性细胞数与足细胞凋亡率呈负相关。当足细胞在体外用DHPG处理时，产生环状AMP并激活CREB(环状AMP反应元件结合蛋白)。选择性mGluR1/5拮抗剂(RS)-1-氨基-1，5-二羧酸、腺苷环化酶抑制剂SQ22536以及RNA干扰抑制mGluR1或mGluR5均可抑制DHPG诱导的cAMP生成和CREB激活。DHPG可抑制氨基核苷诱导的足细胞凋亡和线粒体膜电位的降低，但不能被带有mGluR1或mGluR5基因敲除的SQ22536所抑制。因此，功能性的mGluR1和mGluR5在足细胞中表达，它们的激活可以保护足细胞免受蛋白尿和足细胞凋亡的影响，这一过程至少部分依赖于cAMP。《国际肾脏》(2012年)81,458468；doi：10.1038/ki.2011.406；2011年12月14日在线发布
In non-neuronal cells, glutamate is an extracellular signaling mediator. Since podocytes have glutamate-containing vesicles, we sought to determine glutamate receptor presence and action in glomerular cells. The metabotropic glutamate receptors (mGluR) 1, 5, 6, and 8 were found to be expressed in mouse brain and glomeruli; predominantly in podocytes. In two models of proteinuria (BalB/C mice with puromycin aminonucleoside- and doxorubicin-induced podocyte injury) we found that the selective mGluR1/5 agonist (S)-3,5-dihydroxyphenylglycine (DHPG) attenuated albuminuria and improved the expression of the podocyte marker WT-1. TUNEL staining showed that the number of podocytes undergoing apoptosis was inversely correlated with the number of WT-1-positive cells in glomeruli. When podocytes were treated with DHPG in vitro, they generated cyclic AMP and activated CREB (cyclic AMP response element binding protein). The selective mGluR1/5 antagonist (RS)-1-aminoindan-1,5-dicarboxylic acid, the adenylate cyclase inhibitor SQ22536, and RNA interference knockdown of mGluR1 or mGluR5 all prevented DHPG-induced cAMP generation and CREB activation. DHPG inhibited apoptosis and the decrease of aminonucleoside-induced mitochondrial membrane potential in podocytes but had no effect in the presence of SQ22536 with knockdown mGluR1 or mGluR5. Thus, functional mGluR1 and mGluR5 are expressed in podocytes and their activation protects against albuminuria and podocyte apoptosis, processes that are, at least in part, dependent on cAMP. Kidney International (2012) 81, 458-468; doi:10.1038/ki.2011.406; published online 14 December 2011