Pericyte TIMP3 and ADAMTS1 Modulate Vascular Stability after Kidney Injury
Pericyte TIMP3 and ADAMTS1 Modulate Vascular Stability after Kidney Injury
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DOI：
10.1681/asn.2011080851
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发表时间：
2012-05-01
影响因子：
13.6
通讯作者：
Duffield, Jeremy S.
中科院分区：
文献类型：
--
作者：
Schrimpf, Claudia;Xin, Cuiyan;Duffield, Jeremy S.
肾脏周细胞是损伤后出现的形成疤痕的间质肌成纤维细胞的祖细胞。然而，人们对肾脏周细胞作为微血管细胞的功能以及这些细胞如何从肾小管周围毛细血管分离并迁移到间质空间知之甚少。在这里，我们使用公正的方法来鉴定肾脏周细胞中与体内损伤反应的分离和分化相关的基因，特别关注调节蛋白水解活性和血管生成的基因。肾脏周细胞快速激活解整合素和具有血小板反应蛋白基序 1 (ADAMTS1) 的金属蛋白酶的表达，并下调其抑制剂金属蛋白酶组织抑制剂 3 (TIMP3) 以应对损伤。与脑周细胞类似，肾周细胞在三维凝胶中结合并稳定毛细管网络，并抑制内皮细胞中的金属蛋白水解活性和血管生成信号传导。相比之下，肌成纤维细胞尽管源自肾脏周细胞，但不具有这些血管稳定功能。周细胞衍生的 TIMP3 使毛细血管网络稳定，ADAMTS1 使毛细管网络不稳定。此外，缺乏 Timp3 的小鼠在肾脏中具有由于周细胞过度激活而产生的自发微血管表型，并且更容易受到损伤刺激的微血管稀疏的影响，并伴有旺盛的纤维化反应。总而言之，这些数据支持肾脏周细胞在微血管稳定性中的功能，强调了细胞外蛋白水解活性调节剂在毛细血管稳态中的核心作用，并将 ADAMTS1 确定为肾脏周细胞激活的标志物。
Kidney pericytes are progenitors of scar-forming interstitial myofibroblasts that appear after injury. The function of kidney pericytes as microvascular cells and how these cells detach from peritubular capillaries and migrate to the interstitial space, however, are poorly understood. Here, we used an unbiased approach to identify genes in kidney pericytes relevant to detachment and differentiation in response to injury in vivo, with a particular focus on genes regulating proteolytic activity and angiogenesis. Kidney pericytes rapidly activated expression of a disintegrin and metalloprotease with thrombospondin motifs-1 (ADAMTS1) and downregulated its inhibitor, tissue inhibitor of metalloproteinase 3 (TIMP3) in response to injury. Similarly to brain pericytes, kidney pericytes bound to and stabilized capillary tube networks in three-dimensional gels and inhibited metalloproteolytic activity and angiogenic signaling in endothelial cells. In contrast, myofibroblasts did not have these vascular stabilizing functions despite their derivation from kidney pericytes. Pericyte-derived TIMP3 stabilized and ADAMTS1 destabilized the capillary tubular networks. Furthermore, mice deficient in Timp3 had a spontaneous microvascular phenotype in the kidney resulting from overactivated pericytes and were more susceptible to injury-stimulated microvascular rarefaction with an exuberant fibrotic response. Taken together, these data support functions for kidney pericytes in microvascular stability, highlight central roles for regulators of extracellular proteolytic activity in capillary homoeostasis, and identify ADAMTS1 as a marker of activation of kidney pericytes.