Erythropoietin production by PDGFR-β+ cells
Erythropoietin production by PDGFR-β+ cells
复制标题
DOI：
10.1007/s00424-016-1829-2
复制
发表时间：
2016-08-01
影响因子：
4.5
通讯作者：
Kurt, Birguel
中科院分区：
文献类型：
--
作者：
Gerl, Katharina;Nolan, Karen A.;Kurt, Birguel
肾脏的PDGFR-β表达细胞被认为是促红细胞生成素（EPO）产生的相关位点。这些细胞的起源，它们对肾脏EPO产生的贡献，以及其他器官中的PDGFR-β阳性细胞是否也能够表达EPO尚不清楚。我们在小鼠中解决了这些问题，其中缺氧诱导的转录因子在PDGFR-β（+）细胞中通过诱导缺失von Hippel-Lindau（Vhl）蛋白而稳定。Vhl缺失导致血浆EPO浓度增加600倍，肾EPO信使RNA（mRNA）水平增加170倍，并且红细胞压积值增加高达70%。EPO表达细胞的肾内定位与PDGFR-β表达细胞的区域异质性和分布一致。在多种肾外器官中，只有肾上腺在PDGFR-β（+）细胞中Vhl缺失后显示出显著的EPO mRNA表达。在PDGFR-β（+）细胞中，如果HIF-2 α单独缺失或与Vhl联合缺失，而不是HIF-1 α，则EPO mRNA、血浆EPO和血细胞比容降至低于正常值。用脯氨酰羟化酶抑制剂治疗小鼠，导致野生型小鼠和PDGFR-β（+）细胞中缺乏HIF-1 α的小鼠的EPO mRNA丰度和血浆EPO浓度增加，但对PDGFR-β（+）细胞中缺乏HIF-2 α的小鼠没有影响。这些发现表明PDGFR-β（+）细胞是肾脏中EPO表达的唯一相关位点，并且HIF-2是触发其中EPO表达的必需转录因子。此外，我们的研究结果表明，PDGFR-β（+）细胞产生的EPO可能来自后肾间充质，而不是从神经嵴。
PDGFR-beta-expressing cells of the kidneys are considered as a relevant site of erythropoietin (EPO) production. The origin of these cells, their contribution to renal EPO production, and if PDGFR-beta-positive cells in other organs are also capable to express EPO are less clear. We addressed these questions in mice, in which hypoxia-inducible transcription factors were stabilized in PDGFR-beta(+) cells by inducible deletion of the von Hippel-Lindau (Vhl) protein. Vhl deletion led to a 600-fold increase of plasma EPO concentration, 170-fold increase of renal EPO messenger RNA (mRNA) levels, and an increase of hematocrit values up to 70 %. Intrarenal localization of EPO-expressing cells coincided with the zonal heterogeneity and distribution of cells expressing PDGFR-beta. Amongst a variety of extrarenal organs only adrenal glands showed significant EPO mRNA expression after Vhl deletion in PDGFR-beta(+) cells. EPO mRNA, plasma EPO, and hematocrit fell to subnormal values if HIF-2 alpha, but not HIF-1 alpha, was deleted either alone or in combination with Vhl in PDGFR-beta(+) cells. Treatment of mice with a prolyl-hydroxylase inhibitor caused an increase of EPO mRNA abundance and plasma EPO concentrations in wild-type mice and in mice lacking HIF-1 alpha in PDGFR-beta(+) cells but exerted no effect in mice lacking HIF-2 alpha in PDGFR-beta(+) cells. These findings suggest that PDGFR-beta(+) cells are the only relevant site of EPO expression in the kidney and that HIF-2 is the essential transcription factor triggering EPO expression therein. Moreover, our findings suggest that PDGFR-beta(+) cells elaborating EPO might arise from the metanephric mesenchyme, rather than from the neural crest.